Nilotinib Treatment Post - Allogeneic Stem Cell Transplantation (alloSCT) in Advanced (>CP1) Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL).

Abstract 1176

Poster Board I-198

Therapeutic options in advanced CML (>CP1) and Ph+ALL are limited. AlloSCT is the treatment of choice for these indications, however post-transplant relapse rates are high and outcome is relatively poor. Nilotinib is a second generation, novel tyrosine kinase inhibitor (TKI) that is active in imatinib resistant and advanced CML, producing significant hematologic and cytogenetic responses in all phases of CML and Ph+ALL. Furthermore, nilotinib has activity against most BCR-ABL kinase domain (KD) mutations. We have previously demonstrated that nilotinib therapy pre transplantation allows alloSCT in a less advanced disease phase and with no increase in transplant related toxicity (TRT) in patients with advanced CML and Ph+ALL (Leukemia 23:190-194,2009). The aim of the current phase I/II study (CAMN107AIL03T) was to investigate whether nilotinib administered, at escalating doses starting at 200mg BID, in patients with advanced CML or Ph+ALL pre- and post- alloSCT can intensify remission, reduce relapse and improve outcome without increasing TRT. Nilotinib could also be used pre-transplant at standard doses to improve pre-transplant disease status. Eleven patients have been recruited to the study since July 2008. Seven advanced CML (BC-5, AP-2) and four with Ph+ALL, median age 39 years (range, 21-57), 7 men and 4 women. Previous therapies included chemotherapy for CML BC and Ph+ALL patients, and imatinib for all patients. Cytogenetic and molecular response were assessed by FISH and RQ-PCR (Taqman), respectively and defined as per LeukemiaNet criteria. Two out of eleven patients harbored the Y253H ABL KD mutation detected by the Sequenom assay (Leukemia 21:1318-21, 2007). Five out of eleven patients received nilotinib at the 400mg BID pre-alloSCT and 3 responded [BC „_ CP2 (n=2), AP „_ CP2 (n=1); CHR-1, PCyR-1, CCyR-1] (1 not evaluable). Nine of eleven patients underwent alloSCT (2 are pending) from an HLA-matched sibling (n=5) or alternative donor (n=4). All had myeloablative conditioning (Bu/Cy or Flu/Bu - 6, TBI/Cy-3). Graft versus host disease (GVHD) prophylaxis included CSA and MMF. All patients engrafted in a median of 11 days (range, 9-17) with 100% donor chimerisem. Acute GVHD ( >II) was observed in 5 patients (Gr III/IV - 3) and chronic GVHD in 5 (extensive - 3). No TRM was observed. No transplant-related organ toxicity was observed other than mild to moderate mucositis (n=9). Seven out of the nine transplanted patients received nilotinib at a dose of 200mg BID starting at day +38 (range,30-49) post alloSCT. Did not receive nilotinib: 1 due to severe cytopenia and 1 refused. In four patients nilotinib dose had to be reduced to 100mg BID due to hematological toxicity (2 patients) and non hematological toxicities (2 patients) including rash, pruritus, vomiting and diarrhea. In one patient we observed increased levels of amylase without clinical signs of pancreatitis. Cardiac toxicity or QTc prolongation was not observed. With a median follow up of 7.5 months (range, 4-12), seven out of nine patients are alive, while two died from GVHD and Fusarium fungemia (one each), both 9 months post alloSCT. The first patient was given nilotinib for a very short period and the second patient was never treated, both due to cytopenia. All patients achieved MMoLR (n=8) or CMoLR (n=1) post-alloSCT and the response was durable and maintained with nilotinib therapy without molecular or clinical relapse. No kinase domain mutations were detected post-alloSCT. In conclusion, post-alloSCT nilotinib therapy in patients with advanced CML and Ph+ALL may prevent relapse and disease progression. All patients achieved MMoLR or CMoLR and no patient died from the underlying malignancy. Although a formal maximal tolerated dose (MTD) of nilotinib post alloSCT has not been reached yet, it seems that administration of nilotinib early post alloSCT may be associated with increased toxicity which results in dose reduction in substantial number of patients. The study is ongoing, aiming to recruit 24 patients in 2 years.