Intrathecal prophylaxis with 12 versus 8 administrations reduces the incidence of central nervous system relapse in patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia

The incidence of central nervous system (CNS) disease in adults with acute lymphoblastic leukemia (ALL) is 5%–15% at diagnosis and 5% at relapse with intrathecal chemotherapy (ITC).1, 2 CNS is a known sanctuary site of ALL, and leukemic infiltration into the CNS can lead to significant morbidity and mortality. Disease features such as hyperleukocytosis at presentation,3 common in Philadelphia chromosome-positive ALL (Ph + ALL), increase the risk of CNS relapse. The addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to the backbone of ALL therapies, including ITC, has significantly improved survival. However, with survival prolongation, CNS relapses occurred in 8%–17% of Ph + ALL patients.2, 4, 5 To reduce this incidence and prevent CNS relapses, treatment protocols with hyper-fractionated cyclophosphamide, dexamethasone, vincristine, and doxorubicin alternating with high-dose methotrexate and cytarabine (HCVAD) plus a BCR::ABL1 TKI for adults with Ph + ALL were amended in 2012 to increase the number of prophylactic ITCs empirically from 8 to 12. This study assessed the rate of CNS relapses in adults with Ph + ALL treated with 8 versus 12 ITC. We evaluated 150 consecutive patients ≥18 years of age (median: 51 years, range: 19–84), with newly diagnosed Ph + ALL treated with HCVAD ± rituximab plus imatinib, dasatinib, or ponatinib between July 2001 and January 2019. Patients with CNS disease at diagnosis were excluded. The ITC consisted mainly of methotrexate 12 mg alternating with cytarabine 100 mg given via lumbar puncture during each cycle for up to 6 cycles. Poor risk cytogenetics were defined as the presence of +der(22)t(9;22) or − 9/9p in the absence of high hyperdiploidy.6 Complete molecular response (CMR) was defined as the absence of quantifiable BCR::ABL1 transcripts by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR).7 Assessment of measurable residual disease (MRD) at complete remission (CR) was performed using multiparametric flow cytometry (FCM) and RT-qPCR for BCR::ABL1 transcripts. CNS relapse was defined by the detection of blasts or atypical cells in the cerebrospinal fluid (CSF) in at least two successive evaluations or by findings of leptomeningeal disease on imaging. A landmark analysis was performed at six months, which is the usual time to completion of ITC. Patients who died or were lost to follow-up within six months of therapy were excluded. The CNS relapse-free survival (RFS) was defined from the start of therapy until the time of CNS relapse. Patients who died or relapsed in the bone marrow were censored at time of death and systemic relapse, respectively. Survival was assessed with and without censoring for allogeneic stem cell transplantation (allo-SCT). The time to allo-SCT was handled as a time-dependent variable. The Kaplan–Meier method8 was used to analyze the CNS RFS. The univariate and multivariate Cox proportional hazards regressions were used to identify prognostic factors associated with CNS RFS. Overall, 150 consecutive patients were evaluated; 106 patients (71%) received ≤8 ITC and 44 patients (29%) received >8 ITC. The patient characteristics and univariate and multivariate analysis (MVA) are summarized in the Table S1. The characteristics were similar between groups except more patients in the >8 ITC group received rituximab (43% vs. 22%, p = 0.01) and ponatinib (66% vs. 21%, p ≤ 0.001). Response outcomes to the frontline therapy in patients with ≤8 ITC and >8 ITC were similar (CR 100% versus 100%) but patients with >8 ITC achieved a higher rate of three-month CMR (70% vs. 53% p = 0.08). The median follow-up time of the population was 107.9 months (95% CI 97.3.7–118.7), 125.8 months (95% CI 112.8–138.9) for patients who received ≤8 ITC, and 76.9 months (95% CI 67.4–86.4) for patients who received >8 ITC. CNS relapse occurred in 11 patients (7%, 4 received imatinib and 7 received dasatinib); all had received ≤8 ITC. The incidence of CNS relapse was 10% with ≤8 ITC versus 0% with >8 ITC (p = 0.023). The three- and six-year CNS RFS rates were 92% and 91% in ≤8 ITC cohort and 100% in >8 ITC cohort (three-year CNS RFS p = 0.06; six-year CNS RFS p = 0.04 (Figure 1A). These outcomes remained statistically significant after censoring for allo-SCT (p = 0.046) (Figure 1B). After adjusting for the follow-up time, the MVA showed that >8 prophylactic ITC was significantly associated with decreased rate of CNS relapse (p = 0.03; HR = 0.104, 95% CI: 0.001–0.801). CNS relapses occurred after a median of 17 months (range 6–94). In four of 11 (36%) patients, CNS relapse co-occurred with systemic relapse. One patient experienced systemic relapse after isolated CNS relapse. At time of CNS relapse, BCR::ABL1 transcripts were detected in the peripheral blood or bone marrow of all patients. Treatment of CNS relapse varied from systemic chemotherapy to craniospinal irradiation, but all continued TKI with ITC, consisting of cytarabine, alternating with methotrexate, with hydrocortisone, or combination given twice weekly until CNS clearance. All patients achieved CNS clearance with 4 (36%) experiencing subsequent CNS relapses. The median survival from time of first CNS relapse was 14.7 months (95% CI 8.6–20.8). At the time of data cutoff, only one patient remained alive after CNS relapse. Five patients (50%) died due to infectious complications, one (10%) of intracranial hemorrhage, two (20%) of cardiac arrest, and two from progressive leukemia. Five of the 11 (45%) patients underwent allo-SCT during their treatment course with one allo-SCT preceding CNS relapse. The characteristics and dynamics of CNS relapse for individual patients are shown in Figure S2. This study demonstrates that the incorporation of 12 prophylactic ITC to HCVAD in adults with Ph + ALL significantly reduces the risk of CNS relapse. No CNS relapses occurred with ponatinib, possibly due to its ability to induce early CMR and eradicate the malignant clone systemically rather than its debatable activity in the CNS. HCVAD plus ponatinib has demonstrated superiority over dasatinib9 and imatinib in achieving a CMR at three months,10 a prognostic marker for improved outcomes.7, 11 Penetration of all three TKIs across the blood–brain barrier (BBB) have been studied.12-15 Ponatinib's potential to cross the BBB has been demonstrated in mouse models and scant case-reports exist eluding to its activity. However, in-human studies are necessary to establish its optimal concentration and exposure needed for a meaningful clinical benefit in the CNS.13 On the other hand, dasatinib has been well described to have good CNS activity with its efficacy proportional to dosing.12, 14 Therefore, we compared dasatinib to imatinib and ponatinib which was not significantly associated with less CNS relapses by MVA (p = 0.225; HR: 2.04, 95% CI: 0.46–7.190). We observed CNS relapses in both imatinib and dasatinib groups, specifically when ≤8 ITCs were administered. The number of ITCs administered (>8 ITCs, median of 12 ITCs) was the most consistent variable among the ponatinib group as 24 of 51 patients (47%) switched to dasatinib (n = 19; 79%) or imatinib (n = 5; 21%) after a median of 27 months due to toxicity, intolerance, or its withdrawal from the market in 2013, which is reflective of real-world practice. Until the impact of ponatinib and its interaction with ITC can be investigated further, incorporating 12 ITC should be considered to reduce the risk of CNS relapse in adults Ph + ALL, regardless of the TKI used. Recent advances in chemotherapy-free regimens, such as blinatumomab plus dasatinib16 or ponatinib17 incorporating 12 ITC, have shown promising results; however, the dasatinib-blinatumomab study (N = 63) reports four CNS relapses (6%), at a median follow-up of 27 months. Although total ITCs administered was not reported, its plausible that patients received <12 ITC since majority of the patients received an allograft shortly after the first complete hematologic response. A longer follow-up is needed to determine whether the risk of CNS relapse increases in the absence of CNS-active systemic chemotherapy (such as high-dose methotrexate and high-dose cytarabine), whether >12 ITC are needed, and whether the total number of ITC doses should be influenced by the TKI received. In conclusion, ITC is essential in preventing CNS disease in Ph + ALL, and effectiveness depends on the total number of ITC administered. Our study shows that 12 ITCs should be administered with HCVAD plus a BCR::ABL1 TKI to reduce the risk of CNS relapse. Data collection: Shilpa Paul, Kayleigh Marx, J Michael Savoy, Adam Dippipo, and Nadya Jammal. Data analysis and interpretation: Shilpa Paul, Koji Sasaki, Kayleigh Marx, J Michael Savoy, Adam Dippipo, and Nadya Jammal, Guillermo Montalban Bravo, Elias Jabbour. Manuscript writing: All authors contributed equally. Shilpa Paul: Advisory board or honoraria from Novartis, Pfizer, Amgen. Hagop Kantarjian: Research funding or honoraria from Pfizer, Amgen, Bristol Myers Squibb, Novartis, ARIAD, Astex Pharmaceuticals, AbbVie, Agios, Cyclacel, Immunogen, Jazz Pharmaceuticals. Koji Sasaki: Research funding from Novartis. Honoraria from Otsuka. Advisory board for Takeda, Pfizer, Novartis. Kayleigh Marx, Adam DiPippo, J. Michael Savoy, Nadya Jammal: No conflict of interest. Guillermo Montalban-Bravo: Research funding from IFM Therapeutics. Nitin Jain: Research Funding from Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, Pfizer, Servier, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Incyte, Precision Biosciences, Aprea Therapeutics, Fate Therapeutics, Kite/Gilead, Mingsight, Takeda, Medisix, Loxo Oncology, Novalgen, Dialectic Therapeutics, Newave, TransThera Sciences, Novartis. Advisory Board or honoraria from Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, BMS, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, Beigene, Cellectis, TG Therapeutics, MEI Pharma, Ipsen, CareDX. Tapan Kadia: Grant or research support from AbbVie Amgen, Ascentage, Astellas, Astex, AstraZeneca, BMS, Cellenkos, Cyclacel, Delta-Fly, Genentech, Genfleet, Glycomimetics, Iterion, Jazz, Pfizer, Pulmotech, Regeneron. Consulting for AbbVie, Agios, Daiichi Sankyo, Genentech, Jazz, Liberum, Novartis, Pfizer, Pinot Bio, Sanofi-Aventis, Servier. Honoraria from Genzyme. Nicholas J. Short: Research Grants from Takeda Oncology, Astellas Pharma Inc., Stemline Therapeutics, Inc, and Xencor. Honoraria from Amgen, Jazz Pharmaceuticals, Novartis and Pfizer. Farhad Ravandi: Research funding from Bristol Myers Squibb, Amgen, Macrogenics, Xencor, Selvita, Cellerant. Honoraria from Amgen, Pfizer, Astellas Pharma, Orsenix, Celgene, Agios, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb, Takeda, Jazz Pharmaceuticals, Novartis. Consulting or advisory role for Amgen, Astellas Pharma, Orsenix, Celgene, Jazz Pharmaceuticals, Agios, AbbVie/Genentech, Bristol Myers Squibb, AstraZeneca, Taiho Oncology, Syros Pharmaceuticals, Certara Inc. Eillas Jabbour: Research funding and consultancy from Abbvie, Amgen, Adaptive Biotechnologies, BMS, Genentech, Novartis, Pfizer, Takeda. The data that supports the findings of this study are available from the corresponding author upon reasonable request. The data that supports the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.