Combination Chemotherapy Plus Dasatinib Leads to Comparable Rates of Overall Survival and Relapse-Free Survival As Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Positive Acute Lymphoblastic Leukemia

Abstract

Introduction: The presence of the Philadelphia chromosome has historically been associated with a poor prognosis in patients with acute lymphoblastic leukemia (ALL). Prior studies had demonstrated that the 5-year overall survival (OS) rate among adult patients with Philadelphia-chromosome positive (Ph+) ALL was 25% compared to 41% in Philadelphia-chromosome negative (Ph-) ALL (Moorman et. al. Blood 2007). While hematopoietic stem cell transplantation (HSCT) has long been regarded as the standard of care for adult Ph+ ALL patients despite its significant transplant-related morbidity and mortality, its benefit is less clear in the era of newer-generation tyrosine kinase inhibitors (TKI) such as dasatinib. Methods: We conducted a retrospective study at a single urban transplant center with academic affiliation to analyze the outcomes of adult patients diagnosed with Ph+ ALL between 2005-2018. Patients were treated with either combination chemotherapy plus dasatinib or combination chemotherapy plus dasatinib and allogeneic HSCT. Chemotherapy regimens included hyper-CVAD, Berlin-Frankfurt-Munster-like (BFM-like) protocol, and a regimen developed at the University of Southern California (USC ALL regimen) using pegaspargase (Douer et. al. Journal of Clinical Oncology 2014). All patients in both the transplant group and the non-transplant group received TKI therapy with dasatinib throughout their treatment courses; in the former, patients received dasatinib both prior to and following their transplants. Statistical analysis was performed using the Fisher Exact Probability Test with p-values <0.05 deemed significant. Results: A total of 71 Ph+ ALL patients were included in this study. Forty-three patients (60.5%) were male and the median age at the time of diagnosis was 44 years (range 20-69). Median follow-up time was 15 months (range 1-131). Chemotherapy regimens included the USC ALL regimen in 69.8% of patients, hyper-CVAD in 25.6%, and BFM-like protocol in 7%. While in remission, 31 (43.6%) patients underwent allogeneic HSCT with subsequent post-transplant dasatinib therapy. Median time of dasatinib initiation following transplant was at day 102. Matched related donor transplants were performed in 48% of patients, matched unrelated donor transplants in 24%, and haploidentical donor transplants in 29% of patients. In comparing OS rates, 1-year OS was 92.9% vs. 100% (p = 0.49), 2-year OS was 90.1% vs. 83.3% (p = 0.60), and 3-year OS was 75% vs. 62.5% (p = 0.64) in the allogeneic HSCT group compared to the non-transplant group, respectively (Figure 1). The 3-year relapse-free survival (RFS) rates also proved to be similar at 70.5% in the allogeneic HSCT group and 80.1% in the non-transplant group (p = 0.94, Figure 2). In addition, 37% of patients had a poor prognostic factor of a white blood count (WBC) >30 x 109/L at the time of diagnosis. When comparing rates of OS and RFS between transplant vs. non-transplant patients in this group, there was also no significant difference. Conclusion: This study showed that in the management of adult Ph+ ALL patients, there was no significant difference in OS or RFS between patients who underwent allogeneic HSCT compared to those who received only combination chemotherapy with dasatinib. In addition, prior studies of Ph+ ALL patients treated with either chemotherapy alone or chemotherapy followed by HSCT concluded that the OS rates were approximately 50%, 35%, and 30% at the 1-year, 2-year, and 3-year marks, respectively (Rowe et. al. Blood 2005). Our analysis, however, demonstrated improved rates of survival at all time points for this patient population with the addition of dasatinib. Subgroup analysis of patients with a WBC >30 x 109/L at the time of diagnosis also showed no significant difference in OS between transplant and non-transplant patients despite previous reports showing a survival benefit from HSCT (Huang et. al. Blood 2016). This may be attributed to the fact that our patients received the newer and more potent agent dasatinib compared to imatinib in these prior studies. Since allogeneic HSCT demonstrated no survival benefit in our study and can also introduce risks of serious infectious complications, venoocculsive disease (VOD), and graft-versus-host disease (GVHD) that contribute to patient morbidity and mortality, it may serve a less beneficial role for the Ph+ ALL population in the era of newer-generation TKIs. Disclosures No relevant conflicts of interest to declare.

Quimioterapia intensiva asociada a imatinib en leucemia linfoblástica aguda del adulto, Philadelphia positivo. Experiencia en un hospital público

“…Con el uso de ITK de segunda o tercera genera-ción, se describen aún mayor número de pacientes con EMR negativa precoz; con dasatinib 60% 14 o ponatinib 73% 13 , asociado a mayores efectos adversos. La remisión molecular precoz definiría un subgrupo de pacientes con pronóstico favorable, en los cuales podría ser discutible un TPH en RC1 [11][12][13][14][15] . Esta opción, sin embargo, no ha sido evaluada en ensayos clínicos aleatorizados, por lo que el TPH alogénico en RC1 sigue siendo considerado el estándar.…”

“…Esta diferencia puede deberse, entre otras razones, a un menor acceso a TPH en nuestra serie. Con ITK más potentes, las sobrevidas a 3 años superan el 70% 12,13,18 .…”

“…Los resultados fueron sorprendentes, con tasas de RC de 90%-97% mejorando notablemente el acceso a TPH y la sobrevida global (SG) [7][8][9][10] . Imatinib fue el primer ITK con efecto sobre BCR-ABL1 utilizado en LLA Ph+; más recientemente, se han utilizado otros inhibidores como dasatinib, nilotinib, bosutinib y ponatinib [11][12][13] . A pesar de la mejoría pronóstica, el mayor problema en LLA Ph(+) sigue siendo la expresión de mutaciones resistentes de BCR-ABL1 que inducen a recaída, aún después del TPH.…”

“…A pesar de la mejoría pronóstica, el mayor problema en LLA Ph(+) sigue siendo la expresión de mutaciones resistentes de BCR-ABL1 que inducen a recaída, aún después del TPH. Recientemente se ha observado que aquellos pacientes con patrones sensibles, que logran enfermedad mínima residual (EMR) negativa precozmente, a los 3-5 meses de iniciada la quimioterapia, presentan sobrevida libre de recaída similar con o sin TPH 9,12,14 . No está claro aún cuál es el tratamiento de inducción óptimo, cuál ITK preferir, su dosis y tiempo de uso, como tampoco el rol definitivo del TPH 15 .…”

Comparison of allogeneic hematopoietic stem cell transplantation and TKI combined with chemotherapy for adult philadelphia chromosome positive acute lymphoblastic leukemia: a systematic review and meta‐analysis

“…The baseline characteristics of the articles included in our meta-analysis, all published from 2012 to 2019, are listed in Table 1. In total, the studies enrolled 959 adult Ph+ ALL patients receiving imatinib, [35][36][37][38][39][40][41][42][43] dasatinib, 35,[43][44][45][46] nilotinib, 47,48 or ponatinib. 49 Seven of the studies were prospective.…”