Page 1481 - Hematology_ Basic Principles and Practice ( PDFDrive )

1316 Part VII Hematologic Malignancies

and should be avoided. Although older studies demonstrated that reports of randomized studies in both children and adults demon-
surgical resection of abdominal disease improved outcome, indicating strate that it adds a survival advantage.
the importance of tumor volume, more effective and risk-adapted Toxicity is an important clinical limitation of these regimens in
treatments have made surgical resection unnecessary except for spe- adults, particularly in older patients and in patients who are immu-
cific complications such as obstruction, perforation, fistula, or nosuppressed, in whom severe morbidity and even mortality occur.
bleeding. Therefore, one of the major therapeutic challenges in BL is to develop
Early treatment strategies for BL were modeled on acute lympho- therapies that are as effective in achieving high cure rates as “standard”
blastic leukemia (ALL) regimens that used dose-intense and prolonged regimens but that also improve the therapeutic index and reduce
treatment with induction, consolidation, and maintenance phases. toxicity complications. This approach has been investigated using
These approaches stand in contrast to the significantly less dose- EPOCH-R-based therapy in BL. Based on the efficacy of the regimen
intense regimens used in adults with “intermediate-grade” lymphoma, in a DLBCL study—which suggested that DA-EPOCH overcomes
such as CHOP and CHOP-based regimens, that only produced a the adverse effect of high proliferation, likely because of its infusional
50% to 60% event-free survival (EFS). Although dose intensity and schedule—a study was undertaken in BL and demonstrated a high
18
dose density are important treatment components for BL, later PFS of over 90%. There were very low rates of TLS and other toxici-
studies indicated that shorter treatment durations were equally effec- ties compared with conventional BL regimens and this low-intensity
tive. Furthermore, the recognition that tumor volume is an important therapy is now under investigation in a multi-center study. In the
prognostic feature led to the use of risk adaptive approaches and a setting of HIV infection, a concern with standard BL regimens has
further reduction in treatment for patients with early stage disease. been toxicity and less toxic appear to be more appropriate. 18,19
Several biologic characteristics of BL have helped guide treatment
strategies, including its high proliferative fraction. It has been recog-
nized for years that BL is sensitive to multiple chemotherapy classes, SALVAGE THERAPY
and in endemic BL, cures were occasionally achieved with single-
agent cyclophosphamide. Despite initial sensitivity, however, patients The salvage treatment of relapsed DLBCL should be approached in
frequently relapsed, particularly those with higher volume disease. an individual manner because the choice of treatment is influenced
This apparent dichotomy can potentially be explained by the high by the time to recurrence, prior therapy, medical condition, and the
tumor proliferation rate, resulting in “kinetic” failure. One strategy potential for cure. Although most relapsed aggressive lymphomas
to overcome “kinetic” failure is to increase the dose density through require combination chemotherapy for adequate disease control, it is
frequent chemotherapy administration, a strategy used in most important to recognize that patients with local disease may be salvaged
current BL regimens. Another strategy is to increase the fractional with radiation therapy. Examples include primary mediastinal
cell kill or efficacy of chemotherapy, thereby reducing the number of DLBCL, which can remain local even at relapse, and PTLDs, which
tumor cells that can survive and proliferate between cycles. Hence, may have an isolated resistant EBV clone after chemotherapy.
BL regimens commonly use multiple chemotherapy agents in high A variety of active salvage chemotherapy regimens are available for
doses and alternating cycles. They typically include anthracyclines, relapsed or refractory DLBCL. Platinum-containing regimens, such
epipodophyllotoxins, vinca alkaloids, and alkylators, as well as as ESHAP (etoposide, methylprednisolone, cytosine arabinoside, and
methotrexate and cytarabine, which are cell cycle active agents and platinum) and ICE (ifosfamid, carboplatin, and etoposide), are cur-
take advantage of the high tumor proliferation. These agents, however, rently among the most widely used salvage treatment. It is a com-
are administered in a variety of combinations and schedule, indicat- monly held notion that salvage treatment should include different
ing the empiric nature of the actual combinations. agents from past treatment to avoid drug resistance. Recent evidence
The risks of TLS and propensity for CNS dissemination in BL indicates, however, that sensitivity to apoptosis is a central cause of
also have important treatment implications. All patients should drug resistance and that drug-specific mechanisms are less important.
receive TLS prophylaxis during the first cycle and undergo close Hence, salvage regimens developed around the most active upfront
monitoring of their electrolytes. The high risk of CNS involvement agents should show high activity. The addition of rituximab appears
has prompted the use in the past of relatively high-dose intravenous to enhance the activity of salvage regimens as demonstrated by results
methotrexate and cytarabine, both of which have CNS penetration, with R-ICE (rituximab, ifosfamid, carboplatin, and etoposide) and
and intrathecal administration of these drugs. An important advance ICE, which showed CRs of 53% and 27%, respectively.
has been to reduce intrathecal treatment and eliminate whole-brain Patients with chemotherapy-sensitive disease have the best
radiation for prophylaxis, which has significantly reduced CNS toxic- outcome with ASCT, and this is recommended at initial relapse; in
ity. A study published by the FAB/LMB demonstrated that patients the pre-rituximab era, this approach yielded overall survival (OS) and
with early stage BL had a high cure rate and very low rate of CNS EFS rates in the range of 40% to 50% and 30% to 40%, respectively.
relapse without the use of intrathecal chemotherapy. 17 However, the improvement in upfront curability of DLBCL because
There are multiple highly effective regimens for BL; however, of immunochemotherapy has diminished the efficacy of ASCT at
because of the rarity of the disease (there are only 1200 new cases relapse, which was recently demonstrated in the CORAL study, in
in the United States each year) there are no good comparative which the 3-year EFS of patients who had initially received rituximab
studies of different therapies in BL. A variety of dose-intense short- was merely 21% after ASCT. Of course, patients with chemotherapy-
duration regimens have achieved durable CRs in a high proportion resistant disease do poorly with ASCT and should be considered for
of patients. Included in these are the French LMB and German experimental treatments such as allogeneic SCT. Recently, in B-cell
Berlin-Frankfurt-Munster (BFM) protocols and the National Cancer lymphoproliferative disorders, chimeric antigen receptor T-cell
Institute CODOX-M/IVAC (cyclophosphamide, vincristine, doxo- therapy has been investigated in many different relapsed/refractory
rubicin, and HD-MTX alternating with ifosfamide, etoposide, and settings and has shown some promising activity in DLBCL. 20
high-dose cytarabine; intrathecal methotrexate and cytarabine are The outcome for patients with BL who relapse after or progress
also administered) regimen. These regimens are similar in their drug during initial therapy is extremely poor, and there are no standard
composition, short cycle length, and CNS prophylaxis. Although approaches that have been associated with good outcomes; therefore,
most BL occurs in children, Magrath and colleagues demonstrated experimental approaches should be considered.
that adults have a similar disease outcome when treated with the
same regimen and reported cure rates approximately 90%. Other
groups have confirmed the efficacy of this regimen albeit with lower Late Complications of Treatment and Follow-up
survival rates. In the United Kingdom, Mead and colleagues reported
an overall EFS of 65% at 2 years. The hyper-CVAD regimen has also It is important to recognize that successful treatment may be associ-
been tested in BL with good results (recently with the addition of ated with late complications that may not appear for decades. Among
rituximab). Rituximab is typically used in this disease, and early the major late-term complications are secondary malignancies,