Page 1338 - Hematology_ Basic Principles and Practice ( PDFDrive )

1184 Part VII Hematologic Malignancies

sensitivity and widespread use of assays that can detect this molecular patients, the median DOR was not reached, with three MRs ongoing
abnormality. Although imatinib lacks activity against KIT D816V in at 49, 33, and 19 months at the time of data cut-off. The median
vitro and in vivo, it has led to clinical benefit in patients with alterna- OS was 9.4 months among all patients with MCL, but was not
tive KIT mutations or wild-type KIT. For example, imatinib has reached among responding MCL patients. In addition, the hazard
elicited excellent responses in cases of the well-differentiated SM for death was reduced by 95% in MCL responders versus nonre-
27
variant with either the F522C TM KIT mutation or wild-type KIT; sponders. Symptoms and quality of life, measured by the Memorial
in a patient with familial SM carrying the germline KIT K509I Symptom Assessment Scale (MSAS) and Short-Form 12 (SF-12)
mutation; with deletion of codon 419 in exon 8 of KIT in pediatric survey, respectively, were significantly improved with midostaurin
CM; and in a case of MCL with mutation in exon 9 (p.A502_ treatment. Improved symptoms and quality of life may relate to the
Y503dup). It is also noteworthy that long-term treatment with ability of midostaurin to block IgE-dependent mediator release from
imatinib (400 mg/day) is associated with an almost complete MC MCs in vitro. The drug was generally well tolerated with a manage-
deficiency, which may be of clinical relevance in reactive (nonclonal) able toxicity profile consisting mostly of gastrointestinal side effects,
MCAS and other MC-dependent diseases. including nausea and vomiting, primarily grade 1–2 in nature. These
data support further exploration of midostaurin in combination with
other agents with activity in advanced SM (e.g., cladribine), and
Masitinib evaluation of the drug in ISM patients with refractory MC activation
symptoms.
Masitinib (AB1010), is an inhibitor of Lyn, Fyn, PDGFR-α/β, and
wild-type KIT. After an initial study II trial in patients with ISM or
CM with symptoms unresponsive to prior therapy, masitinib was Other Agents
studied in a phase III, randomized, double-bind trial of 135 patients
with ISM or SSM (108 subjects formally satisfied the WHO criteria Phase I/II trials of denileukin diftitox, everolimus (RAD001), dacli-
for SM). Subjects were randomized to oral masitinib (6 mg/kg daily zumab, thalidomide, and lenalidomide have shown limited or no
in two daily doses) or placebo. The primary end-point of the study activity in small numbers of SM patients. Hydroxyurea has been used
was based on a 75% or more improvement in one or more symptom to control leukocytosis and splenomegaly in patients with a concur-
categories: pruritis, flushing, depression, or fatigue. Of the patients rent AHN such as MPN, CEL/HES, or MDS/MPN. Multiagent,
taking masitinib, 18.7% achieved this endpoint compared to 7.4% intensive chemotherapy is usually reserved for patients with MCL,
of patients taking placebo. At week 24, there was an 18% decrease especially for patients with kinetically active disease, but the results
in the serum tryptase level in the masitinib arm versus an increase of thus far have been disappointing. Anthracycline plus cytarabine-
2.2% in the placebo arm (P <.0001). Also, urticaria pigmentosa based induction chemotherapy is the standard of care for patients
lesions on masitinib therapy decreased by an average body surface with AML who are suitable for high-intensity therapy, including
area of 12.3% versus an increase of 15.9% for the placebo group. those in whom SM is also present. In such cases, treatment of the
Masitinib-associated clinical benefits were generally sustained during AML almost always takes priority, and the finding of the KIT D816V
a two-year extension period. Although treatment was generally well mutation may provide an opportunity to consider the addition of
tolerated, there was an excess incidence of diarrhea, rash, and asthenia KIT inhibitors such as dasatinib or midostaurin to the induction,
in 9%, 6%, and 4% of patients, respectively, in the masitinib group. consolidation, and/or maintenance phases of treatment. However, the
In addition, 24% of patients in the masitinib arm discontinued safety and efficacy of this approach has yet to be validated in the
therapy because of an adverse event, compared with 10% in the context of clinical trials. Other agents have shown activity against
placebo arm. For these patients with lower-risk disease who have a KIT D816V-mutated MCs in vitro, including the multikinase/KIT
normal life expectancy, these side effects need to be weighed against inhibitor EXEL-0862, heat shock protein 90 inhibitor STA-9090,
the potential benefits of the drug in alleviating SM-related proteasome inhibitor MG132, BCL-2 inhibitor obatoclax, hypo-
symptoms. methylating agents azacitidine and decitabine, and the alkaloid
omacetaxine mepesuccinate (homoharringtonine). However, clinical
trial data regarding their activity in patients have not yet been pub-
Midostaurin lished. Finally, several antibodies and antibody-drug conjugates have
been considered for use in advanced SM. For example, the anti-
Midostaurin (N-benzoylstaurosporine; PKC412) is an inhibitor of CD30 antibody-drug conjugate brentuximab vedotin induces growth
+
multiple TKs including wild-type and D816V-mutated KIT, FLT3, inhibition and apoptosis of CD30 MCs. A clinical trial testing
PDGFR-α/β, FGFR1, and VEGFR2. In Ba/F3 cells transformed by brentuximab has recently been initiated in the United States. Other
KIT D816V, the IC 50 of midostaurin was 30–40 nM compared with agents that may be useful for the eradication of neoplastic MCs and
greater than 1 µM with imatinib. A PR with midostaurin in a patient possibly also neoplastic stem cells, include CD33, CD44, CD52, and
with MCL and an associated MDS/MPN, and encouraging responses CD123 monoclonal antibodies.
in a phase II trial of 26 patients with advanced SM led to a global,
multicenter, open-label trial of midostaurin (100 mg twice daily
on 28-day continuous cycles) in patients with ASM, MCL, and Allogeneic Hematopoietic Stem Cell Transplantation
SM-AHN. 28
The trial employed a steering committee and central pathology Until recently, the role of hematopoietic stem cell transplantation
review to adjudicate eligibility, response, and histopathology. Among (HSCT) in advanced SM remained poorly characterized, and only
89 evaluable patients, the ORR was 60%, of which 75% were MRs. on a limited number of case reports and series had appeared. In a
Responses in organ damage (e.g., normalization of cytopenias/red large, multicenter retrospective analysis published in 2014, Ustun
blood cell or platelet transfusion dependence) and liver function and colleagues evaluated the outcomes of 57 SM patients (SM-AHN,
abnormalities, hypoalbuminemia) were observed regardless of KIT n = 38 [AML = 20]; ASM, n = 7; and MCL, n = 12) who underwent
29
D816V status, prior therapy, or the presence of an AHN. The median allogeneic HSCT. Donor types consisted of HLA-matched identical
best reduction in serum tryptase level was −58%. In addition, the (n = 34) and unrelated (n = 17) donors, umbilical cord blood (n =
median change in BM MC burden was −59%, and 57% of patients 2), and haploidentical (n = 1), and three unknown. Responses were
had a ≥50% reduction in BM MCs. After a median follow-up of 26 observed in 70% of patients, including a 16% CR rate. The remain-
months, the median DOR and median OS were 24.1 and 28.7 ing 30% of responses were split between stable disease (21%) and
months, respectively. Median OS in responders was 44.4 months primary refractory disease (9%). All 38 patients with SM-AHN
compared with 15.4 months in nonresponders. Of the 16 patients achieved CR regarding the AHN component, but 10 subsequently
with MCL, 8 responded, including 7 MR (44%); among MCL relapsed with AHN, and half of these patients died.