12th Congress of the European Hematology ... - Haematologica

Myeloproliferative disorders
Chronic myeloid leukemia
0654
SKIN CHANGES ON CONTINUED IMATINIB THERAPY IN PATIENTS WITH PH + CML
Tapan K Saikia, N Hazarika, B.N. Dhabhar
Prince Aly Khan Hospital, MUMBAI, India
Background. We were the first to report the skin changes (generalized
hypopigmentation) caused by imatinib mesylate (IM) in patients with
Ph + CML or GIST (EHA 2004). Subsequent reports from MDACC confirmed
such findings. IM appears to interfere with the melanin metabolism
through the tyrosine kinase pathway and such changes could be different
and more profound among the brown skinned people of India.
Aims. To document the dynamics of skin changes among the Indian
patients who were on regular IM therapy for Ph + CML. Methods. A cohort
of 200 Ph + CML patients at various phases of the disease receiving IM
in a daily dose of 300 mg - 800 mg (children 200 mg daily) were studied
over a median period of 12 months (range 3-72 months). Results. Skin
changes of any kind or severity were noted in 120 (60%) patients. Most
changes were evident within first 6 months of IM and in majority within
first 6 weeks of initiation of therapy. Hypopigmentation alone (usually
generalized) was seen in 75 patients (32.5%), combined hypopigmentation
and hyperpigmentation in 39 (19.5%), hypopigmentation +
extreme thinning of the skin in 3 (1.5%) and the classical skin rash of
grade 3/4 in 2 (1%). Skin changes occurred at all dose levels. Characteristically
the hyperpigmented patches were localized to the facial area
over the forehead and/or in a butterfly pattern across the malar areas and
bridge of the nose. Cosmetically these were disturbing for most of the
patients. There was no sex predilection and lesions were non-itchy. On
continued IM therapy the skin changes remained unchanged. IM dose
was not modified among patients with pigment changes alone. However,
in the 3 patients with extreme thinning of the skin (generalized) causing
easy bruising or desquamation at the nail bases, the dose of IM
decreased to 400 mg (from 600 mg) in 2 and to 300 mg (from 400 mg) in
one. In the 2 patients with classical IM skin rash of grade 3/4, recommended
guideline for therapy was followed. Conclusions. IM causes doseindependent
hypo- or hyperpigmentation of the skin in a significant
number of Indian patients with Ph+ CML. This apparently happens due
to modified melanin metabolism through the tyrosine pathway. Some
of these changes (hyperpigmentation and extreme thinning) are bothersome
from cosmetic viewpoint.
0655
NILOTINIB THERAPY INDUCES RESPONSE IN ADVANCED STAGE CML PATIENTS
INCLUDING THOSE IN BLAST CRISIS AND FAILING PRIOR DASATINIB
M. Koren-Michowitz, 1 Y. Cohen, 1 A. Shimoni, 1 N. Amariglio, 1 A. Kattan,
2 A. Nagler1 1 Chaim Sheba Medical Center, RAMAT GAN; 2 Novartis Pharmaceutical Corporation,
PETACH TIKVA, Israel
Background. The second generation Tyrosine kinase inhibitor (TKI)
nilotinib is 30-50 times more potent than imatinib in vitro against CML
cell lines and is active against most clones with BCR-ABL kinase domain
(KD) mutations; therefore it has been studied in patients (pts) with CML
failing imatinib therapy. Aims. Here, we report the results of thirteen
CML pts with resistance or intolerance to imatinib treated with nilotinib
400 mg bid. Pts and Methods. Mean age of the pts was 55 years (range
26-77), there were 8 men and 5 women, 6 with chronic phase (CP), 5
with blast crisis (BC) (myeloid-3 and lymphoid-2) and 2 with accelerated
phase (AP) CML. Eleven pts were imatinib resistant and 2 intolerant
to imatinib. Four pts were treated with dasatinib prior to nilotinib and
started on nilotinib due to resistance (3 pts) or intolerance to dasatinib
(1 pts). All pts were screened for ABL KD mutations at baseline using a
novel, sensitive, MALDI-TOF based assay (SEQUENOM MassARRAY ®
system, Sequenom, San Diego, CA) designed to detect 27 of the common
ABL KD mutations (Leukemia 2007, in press). Mutation status was
verified by sequencing. Three mutations were found in 2 pts at baseline
including F359V, M244V (same patient, AP) and Y253H (BC). Results.
After a median follow up of 5 months (range 1-9) CHR was achieved in
5/10 pts (BC-3, CP-1, AP-1), 2 BC pts have returned to CP and 1 pt has
maintained a previously achieved CHR (overall hematological response
rate 80%). Pts not achieving CHR included a CP pt with primary resistance
to imatinib and a pt with AP with a transient prior CHR. For 3 CP
12 th Congress of the European Hematology Association
pts it is too early to assess response. CCyR was achieved in 3/10 pts
without a CyR at baseline, one pt has maintained a previously achieved
CCyR and one pt has achieved a major CyR (overall CyR 50%). Nilotinib
was discontinued in 5 pts due to progressive disease (BC-1), performance
of an Allo SCT (BC-1), administration of additional chemotherapy
(AP-1, CP-1) and side effects (CP-1, grade 2 bone pain). One BC pt
has died due to disease progression. Among the four pts with prior dasatinib
therapy, one pt with disease progression on dasatinib and AP before
starting nilotinib have reached a CCyR, one pt intolerant to dasatinib is
maintaining a previously achieved MMR on nilotinib, and two other pts
are too early to evaluate. Following 6 months nilotinib therapy the pt
with AP harboring 2 mutations has not reached a CHR. We observed a
disappearance of the M244V mutation while F359V mutation level has
remained unchanged. An additional pt with myeloid BC achieving CHR
with nilotinib has subsequently acquired the T315I mutation at disease
progression. The most common non-hematological side effects were
bone pain and rash in 5 and 3 pts, respectively, necessitating drug withdrawal
in 1. Conclusions. Nilotinib therapy may result in CHR and CCyR
in advanced stage CML pts including BC, and in those failing prior Dasatinib
therapy.
0656
PEGYLATED IFN-ALFA 2A COMBINED TO IMATINIB MESYLATE (IM) 600 MG/DAY CAN
INDUCE COMPLETE CYTOGENETIC AND MOLECULAR RESPONSES IN A SUBFRACTION OF
CHRONIC PHASE (CP) CML PATIENTS REFRACTORY TO IFN ALONE AND TO IM 600 ALONE
F. Nicolini
Edouard Herriot Hospital, LYON, France
Most CP CML patients are sensitive to IM, but some resist at different
levels. Higher doses (≥600 mg/d) of IM may restore disease sensitivity
of resistant patients to 400 mg/d, but usually fail. In the past, IFN-alfa
has demonstrated its usefulness and is able to induce long-term disease
control, despite important side-effects. Here, we prospectively combined
IM 600 mg/day to PegIFN-alfa2a 90 microg/wk for ≥12 months in
patients exhibiting a CHR but