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Chapter 66 Acute Lymphoblastic Leukemia in Adults 1039

intensification of anthracycline during induction has been tested in Some groups have also instituted a 5–7-day steroid prophase
a variety of prospective clinical trials but has not been shown to defi- before starting the induction therapy. This results in gentle cyto-
nitely improve already high CR rates or to result in significant benefits reduction and reduces the risk of tumor lysis. The achievement of
in DFS. Addition of pulsed cyclophosphamide to induction chemo- rapid cytoreduction during this steroid prophase has also been shown
therapy has been studied with conflicting results. In the CALGB to be of prognostic value in several studies.
8811 trial, addition of cyclophosphamide to the induction regimen In summary, although all of the currently employed induction
was shown to lead to improved responses compared with historical regimens in adults with ALL now routinely result in very high CR
control participants. However, in a prospective, randomized Italian rates of 80% to 90%, none of them has yet translated into the 80%
GIMEMA 0288 study, the addition of cyclophosphamide did not to 85% DFS rates that are routinely achieved in pediatric ALL. In
influence CR rate or survival. adult ALL, DFS generally has been reported to be at 40% to 45% at
L-asparaginase (asparaginase) is also an important component of 3 years and 30% to 35% at 5 years (see Table 66.6). Thus the main
ALL therapy and has been incorporated into most ALL trials begin- problem with the current treatment programs in adult ALL is disease
ning with induction. ALL cells are unable to produce asparagine and relapse from the emergence of resistant disease and not in the failure
are dependent on plasma levels of this amino acid for protein synthe- to achieve CR.
sis. Depletion of asparagine results in inhibition of protein synthesis
and subsequent apoptotic leukemic cell death. Traditionally, native
enzyme derived from Escherichia coli has been used. However, this POSTREMISSION THERAPY
preparation can be immunogenic, leading to hypersensitivity reac-
tions and development of cross-reacting antibodies; this preparation, As mentioned earlier, 80% to 90% of adults with previously untreated
while still used elsewhere, is no longer available for administration ALL achieve CR with induction chemotherapy. However, all patients
in the United States. Polyethylene glycosylated (PEG)–asparaginase, relapse if no further chemotherapy is given. This underscores the need
formed by covalently attaching PEG to the native E. coli enzyme, for effective postremission management strategies for these patients
has been developed and offers lower immunogenicity and a longer in first CR (CR1). As described earlier, adult patients with ALL have
half-life. Douer and colleagues treated 25 newly diagnosed adult ALL traditionally been stratified into SR or HR.
patients (median age: 27 years; range: 17–55 years) with the adult The type of recommended postremission strategy is to be based
ALL BFM protocol in which 14 injections of E. coli asparaginase were on the risk (risk-adapted approach), which implies more aggressive
2
replaced by a single dose of pegaspargase (2000 IU/m IV) on day 16 therapeutic approaches for HR groups compared with the SR group.
of induction therapy. After the single dose, asparagine deamination There have been three tested approaches for postremission therapies:
was complete in all patients after 2 hours and in 100%, 81%, and (1) postremission chemotherapy modules followed by long-term
44% on days 14, 21, and 28, respectively. No allergic reactions maintenance chemotherapy; (2) alloSCT; and least frequently, (3)
or pancreatitis was observed, and a CR was achieved in 24 of the autologous stem cell transplantation (ASCT). Studies using these
25 patients. The CALGB 9511 trial used pegaspargase (2000 IU/ postremission strategies are reviewed later.
2
m subcutaneously, two doses during induction and two during The optimal postremission strategy for SR adult patients is not
first intensification) as part of the five-drug induction regimen. Of clear. Conventionally, consolidation and maintenance chemotherapy
the 85 evaluable patients, those with effective asparagine depletion has been the recommendation for this group of patients, given lower
(defined by enzyme levels >0.03 U/mL plasma for 14 consecutive potential for toxicities and up to 40% to 60% survival at 5 years with
days after pegaspargase administration) had improved DFS and OS this approach. Postremission chemotherapy typically consists of a
compared with those without effective asparagine deletion. Thus, variety of non–cross-resistant chemotherapeutic agents administered
use of pegaspargase is generally safe and effective in adults, and has in treatment “modules” for a total of 6–8 months after achieve-
replaced native L-asparaginase as the agent for asparagine depletion. ment of remission. The postremission modules are typically 4–6
In 2011 the Food and Drug Administration (FDA) approved Erwi- weeks in length and are modeled after successful pediatric regimens
naze (asparaginase Erwinia chrysanthemi) to treat ALL patients who and often consist of consolidation module(s), interim maintenance
develop a hypersensitivity reaction to E. coli-derived asparaginase and modules that often focus on CNS prophylaxis (described in more
2
pegaspargase. 25,000 u/m of erwinia asparaginase given every 48 detail below), and a late intensification module(s), which is often
hours for six doses (for every one dose of pegasparaginase) has demon- quite similar to the induction chemotherapy course. The specific
strated safety and results in effective asparagine depletion in pediatric drugs and the sequence or combinations in which they used are
ALL. Patients receiving Erwinia asparaginase are still at risk for known different for each protocol but typically include cyclophosphamide,
toxicities of asparaginase, including bleeding, clotting, transaminitis, L-asparaginase (or pegasparaginase), methotrexate, cytarabine,
and pancreatitis. To avoid systemic toxicities, a novel preparation of 6-mercaptopurine, vincristine, and doxorubicin. Many of these pro-
L-asparaginase in which L-asparaginase is encapsulated within red tocols have evolved empirically with few randomized trials evaluating
blood cells (GRASPA [erythrocytes encapsulating L-asparaginase]) the impact of any of the modifications that have been developed
has been developed and is in early clinical development in Europe. (see Table 66.6).
One of the regimens that is widely used in the United States and A different approach to postremission therapy has been taken by
that also results in high CR rates of approximately 90% is the hyper- the MD Anderson Cancer Center, which have reported long-term
CVAD (cyclophosphamide, vincristine, adriamycin, and dexametha- results of the hyper-CVAD regimen (also listed in Table 66.6). As
sone) regimen developed at the MD Anderson Cancer Center. The described earlier in the induction section, patients received alternat-
hyper-CVAD regimen differs from the pulsed weekly therapy devel- ing cycles of hyperfractionated cyclophosphamide, vincristine, adria-
oped by the pediatric groups and consists of four cycles of intensive mycin, and dexamethasone hyper-CVAD (courses 1, 3, 5, and 7)
infusional cyclophosphamide, vincristine, doxorubicin, and dexa- alternating with high-dose methotrexate and cytarabine (courses 2,
methasone alternating with four cycles of high-dose methotrexate and 4, 6, and 8) followed by maintenance therapy for 2 years with
high-dose cytarabine for a total of eight intensive treatment cycles. 6-mercaptopurine, methotrexate, vincristine, and prednisone
Because CD20 is expressed on 20% to 40% of pre-B lymphoblasts (POMP). They identified the following factors to be independent
+
and has been noted to be associated with adverse prognosis, the poor prognostic factors for survival: older age, Ph disease, leukocy-
investigators at MD Anderson subsequently added rituximab to a tosis, thrombocytopenia, poor performance status, and hepatomegaly.
modified hyper-CVAD regimen for patients with CD20 expression The 5-year OS for the good-risk (risk score: 0–1), intermediate risk
greater than or equal to 20%. In younger patients (≤60 years of age), (risk score: 2–3), and poor-risk groups (risk score: ≥4) were 62%,
rituximab improved 3-year OS to 75% compared with 47% in the 34%, and 5%, respectively.
historical control participants; however, no difference was seen for In summary, despite attempts to intensify postremission therapy
older adults. The GMALL has substantiated these results and ritux- with high doses of cytarabine and anthracycline, the OS rate of
imab is now routinely used with these regimens. patients in all of the studies published in the past decade is