Philipp le Coutre

All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) is the standard of care for acute promyelocytic leukemia (APL), including high-risk disease. Secondary intracranial hypertension (SIH), historically termed pseudotumor cerebri (PTC), is a recognized but uncommon and potentially therapy-limiting complication of retinoid exposure, reported predominantly in pediatric and young-adult patients and most frequently during induction. We report a 31-year-old man with high-risk microgranular APL in whom SIH was diagnosed during the first ATRA/ATO consolidation cycle. The clinical course included progressive headache, ocular pain, pulsatile tinnitus, focusing difficulties, visual deterioration, and diplopia. Ophthalmological assessment demonstrated bilateral papilledema with marked peripapillary retinal nerve fiber layer thickening despite preserved central visual acuity. Magnetic resonance imaging showed bilateral optic nerve sheath distension, prominent optic nerve heads, mild pituitary flattening, and bilateral transverse sinus stenosis. Lumbar puncture demonstrated an opening pressure of 32 cm H₂O with otherwise unremarkable cerebrospinal fluid; removal of approximately 30 mL resulted in immediate symptomatic improvement. Management consisted of temporary ATRA interruption, therapeutic lumbar punctures, acetazolamide, and individualized ATRA rechallenge and dose titration. Repeated attempts at dose escalation reproduced symptoms, and ATRA was ultimately maintained at a maximally tolerated dose of 30 mg/m²/day while full-dose ATO was continued. Molecular remission was achieved after the first consolidation cycle and remains sustained at 18-month follow-up. This case highlights the importance of recognizing ATRA-associated SIH throughout the treatment course and illustrates a pragmatic strategy for preserving ATRA exposure when standard-dose treatment is limited by neurological toxicity. However, the oncological equivalence of reduced-dose ATRA cannot be inferred from a single case.

In this analysis, we examined the risk of secondary malignancies for tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients. We also collected data on specific risk factors for colorectal cancer. Ninety‐one patients with CML and 76 controls were included and in total 4 (4.4%) secondary malignancies were found in patients and 8 (10.5%) in controls. The risk for secondary malignancies was not significantly elevated for CML patients (p = 0.141). Two (2.2%) CML patients developed colorectal cancer compared to 4 (5.3%) in the reference group. A higher risk for CML patients for colorectal cancer could not be found (p = 0.414).

Introduction. Discontinuation (D/C) of Imatinib or other TKIs in Chronic Myeloid Leukemia (CML) represents an important issue in the management of this disease. It is generally accepted that relapse develops (and treatment must be resumed) when patients (pts) lose Major Molecular Remission (MMR), i.e. when the amount of the BCR-ABL1 transcript, measured in peripheral blood by RT-PCR, exceeds 0.1 %. The Imatinib Suspension And Validation (ISAV) study, which started in 2011, enrolled pts with CML treated with Imatinib who showed no evidence of BCR-ABL1 transcript for at least 18 months before enrollment. Methods. A digital PCR (dPCR) for BCR-ABL1 was performed at the time of Imatinib D/C while a second dPCR was performed when non relapsed patients exited the study, 36 months later. dPCR experiments were performed by the QX200 system (BioRad) in the same lab and using the same methodology. The BCR-ABL1 fusion and ABL1 transcripts were quantified using DigiDrop P210 MasterMix and DigiDrop P210 Positive Control (Bioclarma), according to manufacturer's protocol. The target concentration in each sample was expressed as percentage of BCR-ABL1/ABL1. Results. A total of 107 pts were enrolled in the ISAV study. Relapses occurred in 54 pts (52%); among the 53 non relapsed pts, 41 (77%) presented at least one positive RT-PCR result following Imatinib D/C, and only 12 (23%) maintained PCR negativity throughout the duration of the study. Among the non-relapsed pts dPCR performed at treatment D/C showed positivity in 20.6% of cases (95% confidence interval [C.I.] 9-36%), while 91.1% of pts (95%, C.I. 80-97%) evaluated 36 months later showed a positive dPCR value, although no patient resumed treatment. The evaluation of non relapsed pts by dPCR showed that mean values at D/C were 0.00143% +/- 0.0006 (SE); when tested at study exit, the same pts showed average dPCR values of 0.0115 % +/- 0.002. This difference is statistically highly significant and corresponds to a change of approximately 1 log in the residual tumor burden: from 2x107 to 2x108 cells. There was no correlation between the results of RT-PCR performed during the study and the dPCR status at study exit: pts who tested negative by RT-PCR during the study were uniformly negative in dPCR at D/C but tested positive at study exit in 83.3% of cases; pts who showed at least on positive RT-PCR during the study showed positivity by dPCR in 25% at D/C and in 89.3% at study exit. Finally, half of the pts who tested negative by dPCR at study exit showed dPCR positivity when tested at the time of Imatinib D/C. Conclusions. These results show that during a three year period, the D/C of Imatinib led to the increase of approximately 1 log in the tumour burden of non-relapsed pts, although none of them lost MMR and resumed treatment. These data strongly indicate the need for a long-term monitoring of pts who D/C Imatinib; they also suggest that the functional status of residual CML cells rather than their number could represent the critical factor to predict the tumour load present after 3 years of Imatinib D/C. Disclosures Le Coutre: Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Elena:Novartis: Consultancy; Pfizer: Consultancy. Assouline:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Stagno:Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Il-Yang co.: Research Funding. Fava:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.

7001 Background: In prior clinical trials, ≈40-60% of pts with CML-CP and sustained deep molecular response (MR) maintained TFR after stopping long-term imatinib (median duration: ≈ 5-7 y). The single-arm phase 2 ENESTfreedom study (NCT01784068) is the first to specifically investigate TFR following frontline nilotinib. Methods: Pts with CML-CP with typical b2a2 or b3a2 BCR-ABL1 transcripts, ≥ 2 y of frontline nilotinib, and MR^4.5 (BCR-ABL1^IS ≤ 0.0032%) at prescreening were eligible. Upon enrollment, pts continued nilotinib for 1 y, with RQ-PCR assessments every 12 wk (consolidation [CONS] phase) at a central standardized laboratory. Pts with no assessment worse than MR⁴ (BCR-ABL1^IS ≤ 0.01%), ≤ 2 assessments between MR⁴ and MR^4.5, and MR^4.5 in the last assessment of the CONS phase were eligible to stop treatment (TFR phase). Loss of major MR (MMR [BCR-ABL1^IS≤ 0.1%]) triggered re-initiation of nilotinib (ReRx phase). The data cutoff for this analysis was 30 Nov 2015, when all pts who entered the TFR phase had completed 48 wk of TFR, entered the ReRx phase, or discontinued from the study. Results: A total of 215 pts entered the CONS phase. Of these, 190 stopped nilotinib and entered the TFR phase (median age at baseline: 55 y; median time from first MR^4.5 to study entry: 18 mo; median nilotinib duration prior to TFR: 43 mo [range: 33-89 mo]). At wk 48 of the TFR phase, 51.6% (95% CI: 44.2-58.9%) of these 190 pts were in MMR and had not re-initiated treatment (primary endpoint). Of 86 pts who entered the ReRx phase due to loss of MMR by the data cutoff, 85 regained MMR (1 pt discontinued from the study [pt decision] without MMR 7.1 wk after entering the ReRx phase) and 76 regained MR^4.5 (median time to MMR and MR^4.5 among all pts who entered the ReRx phase: 7.9 wk and 13.1 wk, respectively). No new safety signals were observed on treatment. During the TFR phase, 24.7% of pts experienced musculoskeletal pain (grade 3/4 in 1.1%). Conclusions: These data demonstrate the feasibility of TFR following frontline nilotinib. Nilotinib is the first tyrosine kinase inhibitor to demonstrate successful TFR in a large proportion of eligible pts after relatively short exposure (median: ≈ 3.6 y) Clinical trial information: NCT01784068.

Chronic myeloid leukemia developing after transplantation of solid organs and concomitant immunosuppression is a rare but still significant clinical phenomenon. We here describe an additional case of a 62-year-old male patient developing CML after orthotopic heart transplantation and medication with cyclosporine A, mofetil-mycophenolate, and steroids. Initial antileukemic therapy was imatinib at a standard dose and within 15 months of therapy a complete cytogenetic response was noted. In this report we discuss the clinical implications of these rare but biologically important cases.