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1050 Part VII Hematologic Malignancies

higher OS at 3 years after aSCT in CR2 compared with those with nucleoside analog that is currently approved by the FDA for the
active disease at the time of SCT. treatment of pediatric patients with relapsed or refractory ALL who
Oriol and colleagues reported the outcomes of 263 ALL patients have failed two prior regimens. The response rate CR, CR with
in first relapse treated in four consecutive PETHEMA trials. CR2 incomplete recovery of platelets (CRp), and partial response (PR) in
was achieved in 45% of patients, a rate similar to that in the French pediatric ALL is approximately 30%. Response rates in the adult
LALA trials. The median OS after relapse was 4.5 months, with a population appear to be considerably lower and may be associated
5-year OS of 10%. Factors associated with a favorable outcome after with significant toxicity. Kantarjian and colleagues reported 17%
relapse included age younger than 30 years and CR1 duration of response rate (CR, CRp, PR) with single-agent clofarabine in adults
longer than 2 years. The best subgroup of patients was younger than with relapsed or refractory ALL. Based on the modest single-agent
30 years of age with CR1 longer than 2 years in which the 5-year activity, studies evaluating the role of the combination of clofarabine
DFS and OS were 53% and 38%, respectively. with cytarabine or cyclophosphamide are being conducted. The
Vincristine is an important component of ALL treatment. In Southwest Oncology Group Study S0530 was a phase II trial of a
preclinical models, encapsulation of vincristine into sphingomyelin combination of clofarabine and cytarabine for relapsed or refractory
liposomes or “sphingosomes” has been shown to lead to increased ALL patients (n = 37) and demonstrated a response rate of 17% (CR/
efficacy without increased neurotoxicity compared with conventional CRp), which was not better than that reported as a single agent. The
vincristine. Sphingosomal vincristine administered every 2 weeks in COG is now testing the addition of clofarabine to frontline therapy
relapsed or refractory ALL reported an overall response rate of 14%. in an attempt to improve the outcomes for high-risk children and
A weekly schedule resulted in a higher CR rate of 19% overall, and adolescents.
29% in first salvage treatment. Based on an improved toxicity profile (Table 66.11) CD22 is a commonly expressed antigen on the
and comparable efficacy in relapsed/refractory (RR) ALL, particularly precursor B-cell lymphoblast cell surface that is internalized upon
as a single agent, in 2012 the FDA approved vincristine sulfate ligand binding, which makes it an attractive target for monoclonal
liposome injection (VSLI) for the treatment of adult patients with antibodies and antibody drug conjugates. Epratuzumab, a humanized
Ph-negative ALL in second or greater relapse or whose disease has monoclonal antibody against CD22, also has activity in a subset of
progressed following two or more antileukemia therapies. An ongoing patients with ALL. In a COG pilot study, epratuzumab in combina-
international phase III trial is examining the benefit of liposomal tion with standard reinduction chemotherapy was evaluated in 15
vincristine as frontline therapy of older adults with ALL. pediatric patients with relapsed ALL. There was rapid clearing of
Blinatumomab is a novel bispecific T-cell–engaging antibody surface CD22 antigen, and 9 out of 15 patients achieved a CR. In
targeted against CD3 on T cells and CD19 on leukemia B cells. adult patients epratuzumab has been combined with cytarabine and
When blinatumomab concurrently binds CD3 and CD19, the T cells clofarabine in relapsed/refractory precursor B-ALL. Thirteen out of
are activated and directed to CD19-expressing target B cells, resulting 29 patients responded and five patients had MRD assessments,
in a cytotoxic T-cell response. Among 189 patients with relapsed/ of which one achieved a significant molecular remission. The rate
refractory ALL treated with blinatumomab, 43% achieved CR or CR of response with epratuzumab, clofarabine, and cytarabine appeared
with incomplete recovery of counts (CRi), and 82% became MRD to be greater than historical control of clofarabine and cytarabine
negative. Patients that achieved MRD negativity had higher RFS and (SWOG S0530); however, long-term DFS and OS data are not
OS, 6.9 and 11.5 months, respectively, compared to patients in CR yet available. Given its modest initial response rates, the field has
with MRD, 2.3 and 6.7 months respectively. The FDA granted moved onto the evaluation of anti-CD22 conjugates, described
accelerated approval for the use of blinatumomab in relapsed/ briefly here.
refractory ALL in 2014. A small trial of blinatumomab for relapsed Inotuzumab ozogamicin, a CD22 monoclonal antibody attached
+
Ph ALL has also been completed; however, at the present time, this to immunotoxin calicheamicin, has shown activity in non-Hodgkin
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agent is only approved for Ph B-cell ALL. lymphoma and is currently being evaluated in ALL patients. Inotu-
Nelarabine is a prodrug that is demethylated by adenosine deami- zumab has demonstrated response rates of up to 80% in relapsed/
nase to the deoxyguanosine analog (ara-G). T lymphoblasts are sensi- refractory ALL and 78% of responding patients became MRD nega-
tive to the cytotoxic effects of nelarabine, and this drug has been tive. Veno-occlusive disease and transaminitis are toxicities suggesting
studied in T-cell ALL in the relapsed or refractory setting. DeAngelo off-target drug effects that will need to be evaluated further. Longer
and colleagues treated 26 patients with T-cell ALL and 13 patients clinical follow-up data are expected from ongoing trials regarding
with T-cell lymphoblastic lymphoma with nelarabine. The median DFS and OS. In particular, a randomized phase III trial comparing
age was 34 years (range: 16–66 years). The CR rate was 31% with a inotuzumab to salvage chemotherapy in patients with relapsed/
1-year OS of 28%. Neurotoxicity was seen in many patients. Nelara- refractory ALL to determine efficacy and OS will serve as a registra-
bine is currently approved in the United States for both pediatric and tion trial for this antibody conjugate. Frontline introduction of this
adult patients with T-cell ALL and T-cell lymphoblastic lymphoma agent is also being tested. Inotuzumab, in combination with low-dose
who have failed at least two chemotherapeutic regimens. The COG chemotherapy (cyclophosphamide, vincristine, cytarabine, metho-
has recently completed a study evaluating the addition of nelarabine trexate, dexamethasone, rituximab) is being evaluated in newly
to the frontline setting for T-ALL, but longer follow-up will be diagnosed and relapsed older adult (>60 years of age) ALL patients.
needed to evaluate its impact on progression-free survival. Preliminary feasibility and efficacy data from an ongoing trial at the
Despite the approval of these new agents, patients with relapsed MD Anderson Cancer Center were recently reported. In 26 treatment-
ALL continue to be a challenging subgroup of patients, and additional naive patients, 25 achieved a CR or CRp (overall response rate: 96%)
novel therapies (see later discussion) may improve outcomes by and MRD negativity with 86% progression-free survival and 81%
improving CR2 rates and increasing the percentage of patients who OS at 1 year.
could be candidates for aSCT. Importantly, these agents are now Moxetumomab pasudotox is another antibody–drug conjugate
entering trials in the frontline setting with the hope that they will that consists of an anti-CD22 monoclonal antibody fused to a
decrease relapse rates, obviate the need for rescue therapy, and truncated form of Pseudomonas exotoxin A. In a phase I dose–
improve OS in ALL. escalation study, 21 pediatric patients with relapsed or refractory ALL
were enrolled. The drug was well tolerated. In this heavily pretreated
patient population (median number of prior therapies: four), prelimi-
NOVEL THERAPIES nary efficacy results are encouraging with hematologic improvement
in 41% and CR in 24% of the patients. Moxetumomab is currently
Chemotherapy under investigation in children and young adults with relapsed/
+
refractory CD22 ALL, as well as adults with relapsed/refractory ALL.
Many new agents are being investigated for patients with ALL, Coltuximab ravtansine (CoR) or SAR3419 is an anti-CD19
both in the relapsed and frontline setting. Clofarabine is a purine monoclonal antibody linked to the tubulin inhibitor maytansinoid