Background The Philadelphia chromosome is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). While hematopoietic stem cell transplantation (HSCT) has been regarded as a favorable treatment option in adult Philadelphia‐positive (Ph+) ALL, its benefit is less clear in the era of newer generation tyrosine kinase inhibitors (TKIs) like dasatinib. Methods This was a retrospective study that analyzed the outcomes of adult patients with Ph+ ALL treated with either combination chemotherapy plus dasatinib or combination chemotherapy plus dasatinib followed by allogeneic HSCT. Results A total of 70 patients were included; 30 (42.9%) underwent allogeneic HSCT while 40 (57.1%) received only chemotherapy plus dasatinib. In comparing overall survival (OS) rates, results between the 2 groups were similar with a 1‐year OS of 93.3% versus 100% (P = 0.20), 2‐year OS of 89.8% versus 86.2% (P = 0.72), and 3‐year OS of 76% versus 71.3% (P = 0.56) in the transplant versus nontransplant groups, respectively. The 3‐year relapse‐free survival (RFS) rates were also similar at 70.5% in the transplant group and 80.1% in the nontransplant group (P = 0.94). Subgroup analyses were performed for patients with specific poor prognostic factors (higher white blood count, older age, positive minimal residual disease status), but results again showed no significant survival difference between transplant and nontransplant patients. Conclusions While HSCT has historically led to a survival advantage in Ph+ ALL, the results of our study demonstrate that it may have a less beneficial role in the era of newer generation TKIs such as dasatinib.
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.
Introduction: Haploidentical hematopoietic stem cell transplantation (HSCT) is a potentially curative intervention for various malignant and non-malignant hematological conditions. Its use has led to the near universal availability of donors, but major challenges compared to HLA-matched related donor (MRD) and HLA-matched unrelated donor (MUD) transplants still exist. Although the most frequently discussed complication of haploidentical HSCT is graft rejection or severe/fatal graft-versus-host disease (GVHD), infection remains a significant cause of morbidity and mortality compared to other forms of transplant. Methods: This was a retrospective, single institution study that analyzed the outcomes of 187 patients with various hematological diseases who received allogeneic HSCT with haplo donor transplants, MRD transplants, or MUD transplants from 2011-2018. Conditioning regimens included combinations of fludarabine, busulfan, cyclophosphamide, melphalan, antithymocyte globulin, and total body irradiation. GVHD prophylaxis included either the combination of cyclosporine, tacrolimus, and mycophenolate mofetil (MMF) or tacrolimus and methotrexate (MTX). All patients received anti-viral prophylaxis with acyclovir, anti-fungal prophylaxis with either an azole or echinocandin, and anti-bacterial prophylaxis with trimethoprim-sulfamethoxazole or levofloxacin if the absolute neutrophil count (ANC) was <500 cell/mm3. Statistical analysis was performed using the Fisher Exact Probability Test with p-values <0.05 deemed significant. Results: Of the 187 patients who underwent allogeneic HSCT, 45 (24%) of the transplants were from haploidentical donors and 142 (76%) from non-haplo donors (MRD and MUD). Amongst all patients, median time to neutrophil engraftment (ANC >500 cells/mm3) was 16 days (range 13-25 days). Acute GVHD was present in 41% of haploidentical patients and 42% of non-haploidentical patients (p >0.05). Rates of chronic GVHD were also similar between the two groups at 45% in haplo patients and 48% in non-haplo patients (p >0.05). The 100-day infection-related mortality rate following transplant was significantly higher in the haploidentical group at 9% compared to 1% in the non-haploidentical group (p = 0.03, Figure 1). In addition, the 1-year rate of infection-related mortality after transplant was also significantly increased at 16% vs. 4% in the haplo vs. non-haplo groups, respectively (p = 0.01, Figure 2). The proportion of patients who experienced bacterial and fungal infections over this time period was comparable between the two groups (41% vs. 42% for bacterial infections and 18% vs. 12% for fungal infections in haploidentical patients vs. non-haploidentical patients, p >0.05 for both) while the incidence rate of viral infections was significantly higher in the haplo group at 72% vs. 38% in the non-haplo group (p < 0.001). However, all cases of infection-related mortality were due to bacterial and fungal infections rather than viral with 27% of bacterial or fungal infections leading to patient death in haploidentical patients compared to 7% in non-haploidentical patients (p = 0.02, Figure 3). Conclusion: The results of our study showed that compared to non-haplo transplant recipients, patients who underwent haplo transplants had significantly increased risks of 100-day and 1-year mortality secondary to infections. This finding is supported by prior data demonstrating that there is a longer time to immune reconstitution, specifically of the T-cell subset and dendritic cell subgroup, in the haploidentical population (Chang et. al. Journal of Clinical Immunology 2011). Furthermore, our results showed that the increased risk of infection-related mortality is not due to higher rates of acute or chronic GVHD, implying that the risk may be due to haploidentical transplantation itself as opposed to increased amounts of immunosuppressive therapy. While there was a greater incidence rate of viral infections amongst haploidentical patients, no viral infections led to mortality in either transplant group. In contrast, despite similar rates of bacterial and fungal infections between haploidentical and non-haploidentical patients, these infections led to death more often in the haplo population. These findings are important in considering future approaches to infection prophylaxis and treatment in haploidentical transplant recipients. Disclosures No relevant conflicts of interest to declare.
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