The Efficacy of Tyrosine Kinase Inhibitors with Steroid As First Line Induction Therapy in Ph+ Acute Lymphoblastic Leukemia
Authors: Gurman Gunhan , Merter Mustafa , Ataca Pinar , Ozen Mehmet , Atesagaoglu Berna , Gunduz Mehmet , Pekcan Gultekin , Sahin Ugur , Toprak Selami Kocak , Topcuoglu Pervin , Ozcan Muhit , Ilhan Osman , Atilla Erden 
Published: October 2019

Abstract
Introduction:
Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) is a biologically and clinically distinct variant of ALL and accounts for approximately 20 to 30 percent of ALL in adults. Ph chromosome and BCR-ABL fusion gene have been associated with a poor prognosis in ALL patients especially when patients were treated with chemotherapy alone. Better response rates have been reported with the introduction of tyrosine kinase inhibitors (TKIs) and incorporation of TKI into the treatment regimens. This development has allowed more patients to proceed to allogeneic hematopoietic stem cell transplantation (Allo-HSCT). In recent years some studies evaluated the efficacy of TKIs combined with steroids as first-line induction treatment in Ph+ ALL patients.
Patients and methods:
Here we present 5 patients who were newly diagnosed as Ph+ de novo (n=2) or secondary ALL transformed from chronic myeloid leukemia (n=3) and received TKI plus methylprednisolone (MP) as an induction regimen. All of our patients were male. Additional cytogenetic abnormality was detected in two patients (monosomy 7). This therapy was preferred in 3 patients due to comorbid disease and advanced age. Other patients received the therapy for bridging to allogeneic stem cell transplantation. Three patients received imatinib 800 mg daily and 40 mg/m2 MP for 45 days, one patient received dasatinib 140 mg daily and 60 mg/m2 MP for 32 days. TKI treatment after the induction has been continuing in maintenance therapy in all patients, except one patient whose TKI treatment was interrupted due to Allo-HSCT. One patient had a history of resistance to imatinib, nilotinib and dasatinib while he was in chronic phase of chronic myeloid leukemia. Therefore he was treated with bosutinib 500 mg daily plus MP 60 mg/m2 for 32 days. After completing of induction therapy 3 patients received 6-mercaptopurine 70mg/m2 daily, methotrexate 20mg/m2 weekly, vincristine 2 mg/day in every two months, MP 40mg/m2 for 5 days in every month and TKI daily as the maintenance therapy. Central nervous system (CNS) involvement was detected in two patients during the induction treatment on days 30 and 65, respectively. One of them received high dose methotrexate and then underwent Allo-HSCT from an HLA identical sibling donor at fourth month of diagnosis. The other patient was ordered cranial and spinal irradiation together with intrathecal chemotherapy.
Results:
Four patients achieved complete hematologic remission (CHR) at day 22 and one patient achieved CHR at day 45. Complete molecular remission was not obtained in our patients after the induction therapy. After a median follow-up of 7 months (range 3-22), four patients are alive currently. One patient died due to pulmonary infection after 22 months of diagnosis and he was still in CHR at the time of dead. Patient characteristics are given in table.
Conclusions:
Our observations suggest that TKI plus steroid therapy as the first line treatment for remission-induction in Ph+ ALL has been more tolerable and associated with less toxicity. Despite the poor prognostic effect of Ph chromosome in ALL patients, TKI plus steroid regimens may improve outcome and may allow to patients to proceed to Allo-HSCT. As shown among the elderly Ph+ ALL patients, this regimen might also be appropriate for younger Ph+ ALL patients.
Table: Patient characteristics Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Age 69 65 38 70 29 WBC count at presentation (x10 9 /L) 3500 46000 6000 26500 232000 BCR-ABL fusion protein (kD) 190 190 210 210 210 TKI (dose) Imatinib(800mg) Imatinib(800mg) Imatinib(800mg) Bosutinib(500mg) Dasatinib(200mg) BCR-ABL (FİSH)% at presentation 96 90 85 90 - BCR-ABL ratio (RT-PCR) at presentation 3,8 - 30,76 40,9 2,7 BCR-ABL ratio (RT-PCR) at day 22 0,0006 0,1411 0,2964 25 0,2794 Disease status at days 22&45 Hematologic Remission Hematologic Remission Hematologic Remission Hematologic Remission Hematologic Remission

Disclosures
No relevant conflicts of interest to declare.