Page 1055 - Hematology_ Basic Principles and Practice ( PDFDrive )

938 Part VII Hematologic Malignancies

Molecular markers and MRD serve to distinguish favorable from 24%. Patients who are primary refractory to at least one cycle of
unfavorable subsets, although it needs to be recognized that ostensibly HiDAC-based induction therapy do equally poorly, with a subse-
favorable molecular groups of older patients carry a higher risk of quent CR rate of 22%, median CR duration of around 9 months,
relapse than what would be expected for younger patients. and survival of 3.8 months.
The goal of salvage therapy is to recapture a remission or at least
achieve sufficient reduction of disease burden (absence of circulating
Maintenance Therapy blasts, marrow blasts <10%) to transition patients to HSCT. Five-
year survival expectations following HSCT vary from 30% to 40%
Maintenance therapy (i.e., additional therapy following consolida- (first relapse/second CR) to <10% (refractory relapse), but remain
tion) aims to improve the quality of remission, eliminate residual superior to nontransplant therapies across all scenarios.
disease, and maximize the chances to remain disease free. The concept There is no one standard salvage regimen. An intensive che-
is effective in some acute leukemias (ALL, APL), but to date has not motherapy regimen may benefit the few patients with favorable
led to any appreciable improvement in the outcome of patients prognostic features at relapse. Commonly used intensive regimens
with AML. are fludarabine, cytarabine, G-CSF (FLAG), fludarabine, cytarabine,
The antileukemic effect of the immune system is displayed in the idarubicin (FAI), high-dose cytarabine, mitoxantrone (HAM),
graft-versus-leukemia effect following allogeneic HSCT (not if T-cell mitoxantrone, etoposide, cytarabine (MEC), and cytarabine,
depleted), resulting in decreased relapse rates. Initial studies focused daunorubicin, etoposide (ADE). Outcome is similar with any of
on stimulation by IL-2 of immune effector cells such as tumor- the combinations. The MEC regimen is not infrequently associ-
specific cytotoxic lymphocytes and natural killer cells. Although IL-2 ated with severe mucositis. Large randomized studies are rare. One
has demonstrated antileukemic activity in preclinical models, not one international multicenter trial randomized 326 patients ≥55 years of
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study applying low-dose IL-2 (high doses of IL-2 were not feasible age with relapsed and refractory AML to cytarabine 1 g/m daily for
because of drug-related toxicities) showed any improvement of 5 days or cytarabine plus clofarabine. CR rate and EFS were superior
disease-free or OS. Only with the combination of IL-2 plus histamine in the combination arm but the primary OS endpoint was not met.
dihydrochloride could an improvement of leukemia-free survival at Another more recent multicenter study randomized 711 patients
3 years be demonstrated when compared with a randomized observa- with first relapse and refractory AML ≥18 years of age to cytarabine
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tion cohort (40% versus 26%; p = .01). The benefit was restricted to 1 g/m daily for 5 days versus the combination of cytarabine with
patients in CR1 and did not extend to OS. Recent success with vosaroxin, a first-in-class anticancer quinolone derivative. Without
chimeric antigen receptor-transfected T cells and the emergence of an increase in early mortality, the combination arm achieved signifi-
bispecific T-cell antibodies (although harder to apply in AML than cantly higher CR rates (30.1% versus 16.3%, p = .00001) and OS
lymphoid malignancies) has revived the specter of cellular therapy in benefit (median 7.5 versus 6.1 months; p = .06; stratified = 0.02),
maintenance strategies. which was more obvious if patient groups were censored for subse-
Other concepts have been developed based on lenalidomide and quent allogeneic HSCT (median 6.7 months versus 5.3 months, p =
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HMAs (azacitidine, decitabine), including following HSCT. Results .02). Benefit was greatest in patients aged ≥60 years and those with
as to their impact remain inconclusive and maintenance therapy early relapse.
remains investigational. Any of these strategies only rescue a minority of patients with
AML relapse. It therefore remains imperative to pursue more effective
treatments with investigational agents through clinical trials.
Therapy: Salvage

Therapy: Investigational
Most patients with AML relapse and do so within the first year fol-
lowing achievement of remission. In an analysis of 1069 consecutive
AML patients in first CR who were treated and followed at the MD Anti-CD33–Directed Therapy
Anderson Cancer Center, the risk for treatment failure was 69%,
38%, 17%, 8%, and 7% in the first to fifth year, respectively. With CD33 is a cell surface antigen that is present in more than 80% of
a 6-year relapse-free survival of 84% for patients who were alive and patients with AML but is absent from pluripotent hematopoietic
disease free at 3 years, it is reasonable to consider patients cured once stem cells. GO is a humanized anti-CD33 monoclonal antibody
in CR for at least 3 years. For patients over 60 years of age, relapse-free linked to the DNA-binding cytotoxin calicheamicin. As a single
survival was only 56% and therefore a substantial relapse risk persists agent in relapsed/refractory patients with AML, it achieved response
without any discernible “safe haven”. rates close to 30% and resulted in GO’s accelerated approval in
The prognosis for patients in relapse remains poor, but outcomes the year 2000 by the US Food and Drug Administration (FDA).
are more heterogeneous than first impressions suggest. An important Subsequent combinations of GO with chemotherapy demonstrated
predictor for prognosis is the duration of first remission. In a study hepatic toxicities (in particular sinusoidal obstruction syndrome),
of 243 patients with AML in first relapse, the likelihood of CR was which were not observed before. This problem was largely resolved
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60% if the duration of first remission exceeded 2 years and 19% if by reducing GO doses to as low as 3 mg/m in combinations. The
it was shorter than 1 year. Treatment was not associated with prog- expanded spectrum of toxicities plus the observation that GO failed
nosis. In a multivariate analysis of 667 patients in first relapse, a to improve outcome of patients in a large randomized trial by the
prognostic score was derived from four clinical parameters (duration Southwest Oncology Group (SWOG S0106) led the FDA to revoke
of first remission, karyotype at diagnosis, age at relapse, and previous the approval in 2010 and GO was voluntarily withdrawn from the
HSCT or not) that identified three risk groups: a) favorable group: market (except for Japan). However, subsequent randomized trials
CR 85% and 5-year OS 46%; b) intermediate group: CR 60% and in which GO was combined with standard chemotherapy produced
5-year survival 34%; c) poor risk group: CR 18% and 5-year survival favorable results. A metaanalysis of five randomized trials (including
4%. In another prognostic model for relapsed/refractory AML, SWOG S0106) with a total of 3325 patients can be summarized as
disease status (relapse <12 months), FLT3-ITD mutation, and high- follows: 1) GO does not increase remission rate; 2) although early
risk cytogenetics were independent adverse prognostic factors for OS mortality is higher in GO-treated patients, OS is improved as the
and event-free survival (EFS). Three subgroups with different out- reduction in the relapse rate of GO-treated patients far outweighs
comes at 2 years were identified: a) favorable (no adverse features): early mortality; 3) the survival benefit is mostly seen in patients with
OS 58%, EFS 45%; b) intermediate (one adverse factor): OS 37%, favorable and intermediate-risk cytogenetics, but not with adverse
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EFS 31%; c) poor (≥ two adverse factors): OS 12%, EFS 12%. karyotype; 4) doses of 3 mg/m are as effective as higher doses and
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Prognosis is worse for patients after more than one salvage attempt, were associated with fewer early deaths. In other studies, GO has
but even then 1-year survival probabilities vary between 2% and also been shown to be effective and safe for patients with APL.