Molecular remission in advanced acute promyelocytic leukaemia after treatment with the oral synthetic retinoid Tamibarotene

Abstract

Although the vast majority of patients with acute promyelocytic leukaemia (APL) are cured by all-trans retinoic acid (ATRA) combined with chemotherapy, approximately 20% of cases still relapse. Arsenic trioxide (ATO) is the best treatment option for relapsed APL, inducing a second molecular complete remission (CR) in nearly 80% of cases (Sanz et al, 2009). In addition to ATO, other effective molecularly-targeted drugs have been developed to overcome ATRA resistance. Among these, tamibarotene is a synthetic specific retinoic acid receptor (alpha/beta) agonist that was successfully used in Japan before the advent of ATO for the treatment of ATRA-resistant APL (Tobita et al, 1997). Compared to ATRA, tamibarotene is 10 times more potent as it shows lower affinity for the cellular retinoic acid binding protein allowing for greater drug availability in the nucleus (Ohnishi, 2007). To the best of our knowledge, the efficacy of tamibarotene in APL patients who have relapsed after ATO has not been reported so far. Here, we describe a patient with advanced APL who was successfully treated with tamibarotene for a second haematological relapse developed after several treatments including ATO and allogeneic stem cell transplantation. A 44-year-old female was diagnosed in February 2005 with APL intermediate-risk according to Sanz et al (2000). Bone marrow cytogenetic (fluorescence in situ hybridization) and molecular biology (reverse transcription polymerase chain reaction) tests confirmed the presence of t(15;17) and PML/RARA fusion gene (bcr1 type) respectively, in marrow leukemic cells. She received front line treatment with simultaneous ATRA and chemotherapy as reported (Avvisati et al, 1996). During the induction phase the patient developed a severe differentiation syndrome that was treated with high doses of dexamethasone and temporary discontinuation of ATRA. Complete haematological remission was achieved at the end of induction therapy and molecular remission was confirmed after consolidation. She then received maintenance for 2 years with low-dose chemotherapy and intermittent ATRA until October 2007. In November 2007, the first relapse was documented at both molecular and haematological level. Given the availability of a human leucocyte antigen (HLA) identical sibling donor, salvage therapy was planned with ATO followed by allogeneic bone marrow transplant (HSCT). The patient achieved a second molecular CR after one month of a combination therapy with concomitant ATRA (standard dose) and ATO at the conventional dose of 0·15 mg/kg. She then received consolidation therapy with the same combinatorial scheme for a total of three courses. In July 2008, while still in molecular CR, the patient underwent HSCT from a HLA-identical sibling. Neutrophil and platelet engraftment were detected at day + 17 and + 22, respectively. Complete molecular remission and full donor chimerism were confirmed by molecular and cytogenetic analysis respectively, at day +90 post-transplant. In March 2009, a second molecular and haematological relapse (60% blast infiltration in the marrow) was diagnosed, and consequently immunosuppressive therapy was discontinued. The patient was enrolled in the STAR-1/INNO-507-P2 protocol consisting of oral tamibarotene (Cortes-Franco et al, 2009). The study was approved by our Institutional Review Board. The drug was given at 6 mg/m2 per d for a total of 56 d. Bone marrow evaluations were carried out at days 57 and 85 after start of tamibarotene. A complete molecular remission and a full donor chimerism were documented in the marrow at both time points. Two months later she presented with paresthesia and tremors. Cerebrospinal fluid (CSF) examination and craniospinal magnetic resonance imaging (MRI) identified morphologic central nervous system (CNS) relapse while morphological and molecular CR persisted in the marrow. The disease was resistant to triple intrathecal therapy (cytarabine, methotrexate and prednisone) with persistence of blast cells in the CSF after seven intrathecal injections. She thereafter received fractionated craniospinal radiotherapy (23·4 Gy for cranial and 11·2 Gy for spinal radiotherapy respectively) and achieved CSF clearance. Bone marrow molecular remission was documented 6 months after tamibarotene. At this time, ATO at 0·15 mg/kg per d for 5 d a week was again planned as systemic treatment. However, due to increasing QTc interval and grade III haematological toxicity the patient received only a total of 21 doses of the scheduled therapy. At present (May 2010), the patient is in 3rd molecular CR and with persistent full donor chimerism. Although tamibarotene has been approved in Japan as a salvage therapy for ATRA-refractory and/or relapsed APL, no clinical trials or case reports regarding this agent have been reported in the US and Europe. In addition, tamibarotene has not been evaluated as a salvage therapy in ATO-refractory APL patients nor in those relapsing after HSCT. Our patient entered a third molecular remission after 53 d of treatment with tamibarotene. This agent was well tolerated and, contrary to ATRA, did not induce a differentiation syndrome in our patient. A graft-versus-leukaemia effect is very unlikely to be an additive factor for this third remission because immunosuppressive therapy was withdrawn 2 months before the second relapse. Interestingly, as it has been reported for ATRA, this new retinoid showed no protective effect for the CNS as the patient underwent CNS relapse while in molecular CR in the marrow. After blast clearance of the CSF following irradiation, ATO was given as systemic therapy because of some reported evidence that it would cross the blood-brain barrier (Au et al, 2008). In conclusion, this is the first demonstration that tamibarotene is active and apparently well tolerated in advanced APL relapsing after ATO and HSCT. More patients treated with this agent are needed to better confirm and validate our observation. Dr Scott Wieland is employed full-time by CytRx Corporation, Los Angeles, CA, USA. The tamibarotene study was supported by CytRx. All other authors declare no conflict of interest.