Purine Analogues Based Induction Regimen Followed By Allo-HSCT Is An Effective Treatment Modality Of Philadelphia Chromosome-Positive Acute Myeloid Leukemia-Retrospective Analysis Of Polish Adult Leukemia Group (PALG)
Authors: Wierzbowska Agnieszka , Szmigielska-Kaplon Anna , Pluta Agnieszka , Wawrzyniak Ewa , Grosicki Sebastian , Helbig Grzegorz , Knopinska-Posluszny Wanda , Gromek Tomasz , Seferynska Ilona , Lech-Maranda Ewa , Holowiecki Jerzy , Robak Tadeusz 
Published: October 2019

Abstract

Background
Philadelphia chromosome positive acute myeloid leukemia (AML Ph+) is a rare hematological malignancy with dismal prognosis. It comprises 1-2% of all cases with AML. Overall survival (OS) of AML Ph+ patients (pts) is around 6 months irrespective of the treatment modalities. The best treatment option has not been clearly determined.

Material and methods
We present a retrospective, multicenter analysis of AML Ph+ cases diagnosed in last 12 years in Poland. We searched our onsite registries for the pts diagnosed with AML without preceding history of chronic myeloproliferative neoplasm. All the pts had Ph chromosome present in the classic GTG cytogenetics performed at the time of diagnosis of AML. Patients with biphenotypic acute leukemias were excluded from the analysis. To our knowledge, this analysis covers the biggest group of pts with AML Ph+.

Results
During the 12 years period, 17 adult pts with de novo AML Ph+ were identified among 1221 newly diagnosed AML pts in 13 hematological departments cooperating in PALG clinical trials. The overall incidence with de novoAML Ph+ among all AML patients was 1,39%.

Clinical characteristics
The AML Ph+ group consisted of 11 men and 6 women with the median (Me) age of 36 years old (range 18-70 y). The median WBC count (25,3 G/L), peripheral blood basophiles percentage (0,5%) and Hgb level (9.2 g/dl) at diagnosis in AML Ph+ did not differ significantly compared to that reported for AML of all types (WBC 13,4 G/L; Baso 0,3%; Hgb 8,5 g/dlL respectively). However, the AML Ph+ group had a higher PLT count at diagnosis than AML Ph- patients (108 vs 43,6 G/L, p50 G/L p<0.0001) and a higher leukemic infiltration of bone marrow (78% vs 58%; p<0.02). Splenomegaly, hepatomegaly and lymphadenopathy as assessed by physical examination were similarly common in AML Ph+ and Ph−. The majority of AML Ph+ were diagnosed as M2 (47%) and M4 (29%) according to FAB classification. The M0 and M1 FAB subtypes consisted equally of 12%. In nearly all cases of AML Ph+ the blasts expressed CD13, CD33, CD34 and CD117. Bone marrow cytogenetic results at diagnosis were available for all 17 pts. The t(9;22) was the sole chromosome abnormality in 11 cases. Six AML Ph+ cases exhibited additional aberrations besides t(9;22) and 5 cases had at least 1 extra abnormal related clone. One variant t(9;14;22) was also observed occurring as the sole chromosomal abnormality.
Treatment Response and Outcome: All but two AML Ph+ pts received standard induction chemotherapy according PALG AML protocols (DA-6 pts; DAC-8 pts and DAF-1 pt) (Holowiecki J; JCO 2012). One patient received FLAG-Ida induction regimen and one low-dose Ara-C. Five pts underwent allogeneic stem cell transplantation (allo-SCT). After first course of induction therapy 8/16 pts (50%) achieved the complete remission (CR) and one patient died early. The CR rate in pts who received more intensive first induction regimen with purine analogues (PNA) (DAC; n=8, DAF; n=1 or FLAG-IDA; n=1) was higher than in the standard DA group (70% vs 16,7% respectively; p=0.056). All 7 patients who did not respond to first induction course received second induction cycle (CLAG-M-6 pts, and DAC +imatinib (IM) − 1 patient). The overall CR rate was 75% and is the highest published in the literature. The only factors associated with higher probability of CR achievement after one course of induction were WBC >50 G/L (p=0.032) and more intensive induction therapy with PNA (p=0.034) in univariate analysis. The median OS of all patients with AML Ph+ was 7,1 months (mo). Higher (>100 G/L) PLT count, achievement of CR and allo-SCT were associated with longer OS in univariate analysis (p=0.037; p=0.045 p<0.01 respectively). However, in multivariate analysis the only factors that influenced OS were CR achievement (HR 10,6; 95%CI: 1.18-86.33; p=0.034). Five out of 17 pts received off label IM at different points of treatment course. Surprisingly, IM had no significant impact on OS in our group.

Conclusions
AML Ph+ has an aggressive clinical course and short OS. More intensive induction regimens with purine analogs increase response to treatment and make CR rate comparable to AML Ph -. The CR achievement and allo-SCT play a pivotal role in long term survival of AML Ph+ patients.

Disclosures:
Off Label Use: Imatinib in Ph+AML.