Maintenance Therapy with Nilotinib (Tasigna) Post Allogeneic Stem Cell Transplantation (AlloSCT) for Advanced (>CP1) Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL)
Authors: Nagler Arnon , Volchek Yulia , Bloom Nira , Somech Raz , Yerushalmi Ronit , Shimoni Avichai 
Published: October 2019

Abstract
Abstract 2011
AlloSCT is the treatment of choice in advanced CML (>CP1) and in Ph+ ALL. However, the post transplant relapse rate is high and outcome is rather poor in this setting. Nilotinib (Tasigna, Novartis Pharmaceuticals) is a very effective, second generation, novel TKI. Reduction of tumor mass pre- and maintenance therapy post alloSCT, may improve response rate and reduce transplant related toxicities (TRT) and relapses. The aim of the current study (CAMN107AIL03T) was to investigate whether nilotinib administration pre-alloSCT (400mg BID) and at escalating doses of 200–400mg BID post-alloSCT will intensify remission, reduce relapse and improve outcome without increasing TRT in pts with advanced CML and Ph+ ALL. 24 pts (M-13, F-11) participated in the study. The median age was 36 years (range, 18–58). 17 pts were with advanced CML (BC-10, AP-7) and 7 with Ph+ ALL. Cytogenetic and molecular responses were assessed by FISH and RQ-PCR (Taqman, LeukemiaNet and Eutos criteria). 5 pts harbored ABL kinas domain mutations by Sequenom assay (Y253H-2, A397P-1, E255K-1, M351T-1). 9 pts received nilotinib (400mg BID) pre-alloSCT and 6 responded (2 are too early to evaluate) (BC- CHR–2, BC - CCR-2, AP - PCR-1, AP - CHR-1). 22/24 pts underwent alloSCT (2 are pending) from an HLA-matched sibling (n=11), matched unrelated (n=8) or alternative donor (CB-2, Haplo-1). All, but one, had myeloablative conditioning (Bu/Cy or Flu/Bu-14, TBI/Cy-7). Graft versus host disease (GVHD) prophylaxis included CSA and methotrexate or MMF. 21/22 pts engrafted in median day+13 (range, 9–38) with 100% donor chimerism. TRT included mucositis in all pts, encephalitis-2, pericarditis-1, VOD-1 and infection-3. 3 pts died very early post transplant from sepsis and multi organ failure. Acute GVHD ≥ Gr II was observed in 10 pts (III-IV in 5). Chronic GVHD was observed in 15 pts (extensive – 9). Sixteen of the 22 transplanted pts received nilotinib (200mg × 2/d – 10, 300mg × 2/d – 6) starting at median day +38 (range, 30–158) post alloSCT. 6 pts did not receive nilotinib post alloSCT due to early death -3, progressive disease -1, severe pancytopenia -1, refusal -1. No pt received the planned 400mg BID dose. In 9 pts nilotinib administration was delayed due to either liver abnormalities -3, severe thrombocytopenia -3 or infection -3. Nilotinib dose had to be reduced (n=4) or stopped (n=3) due to Gr III-IV non-hematological toxicities -5 pts, mainly abnormal liver function tests -4 in combination with pruritus -1, vomiting -1 and abdominal pain -1, or hematological toxicities -2 pts. In 1 pt we observed increased levels of amylase without clinical signs of pancreatitis. QTc (470 msec) prolongation was observed in 1 pt. All, but 2 pts achieved MMR post alloSCT and 6 of them (CML) converted to CMR following nilotinib therapy. Response was durable and maintained. Only in 1 pt with disease progression kinas mutation (G205E and F359V) were detected. With a median follow up of 14.5 months (range, 0.5–36) 12 pts are alive while 12 died (Infection -5, GVHD -3, TTP-1, disease progression -3). In 2 pts disease progressed but responded to further therapy. 5 of 6 pts that did not receive nilotinib died (early death post AllSCT -3, disease progression -1, GVHD Gr IV -1). Immunological evaluation pre- and post nilotinib administration disclosed no significant change in T, B and NK cell numbers and T cell mitogenic response to PHA and anti CD3. Thymic output (TREC) and receptor repertoire (Spectrotyping) analysis indicates continuous thymopoiesis in 8/13 evaluated pts. NK cytotoxic activity against K562 increased in 9/15 evaluated pts. In conclusion, post alloSCT nilotinib maintenance therapy in extremely high risk pts with advanced CML and Ph+ ALL may prevent relapse and disease progression as 1) pts achieved MMR and 6 converted to CMR with nilotinib therapy and 2) only 5/16 pts that received nilotinib post alloSCT progressed [in 4 of them nilotinib could not be administrated as per protocol because of side effects (n=2) or low compliance (n=2)]. Although a formal maximal tolerated dose (MTD) of nilotinib post alloSCT has not been reached, it seems that administration of nilotinib early post alloSCT may be associated with increased toxicity. nilotinib administration post alloSCT does not impair immunological reconstitution, while GVHD incidence seems not to be reduced. Based on these data we would recommend nilotinib maintenance therapy post alloSCT in pts with advanced CML and Ph+ ALL.

Disclosures:
Nagler: Novartis: Honoraria, Research Funding. Off Label Use: Nilotinib (Tasigna) for reduction of tumor mass pre- and maintenance therapy post alloSCT in patients with CML and Ph+ ALL (novel TKI).