Abstract
Background/Aim: Autologous hematopoietic stem cell transplantation (ASCT) after high-dose chemotherapy is used to treat relapsed malignant lymphomas. Radiation therapy (RT) is applied after ASCT. We compared the incidence of myelosuppression after RT with and without autologous peripheral blood stem cell transplantation (auto-PBSCT). Patients and Methods: We retrospectively analyzed 20 patients with malignant lymphomas who received RT, six of whom underwent auto-PBSCT. Univariate analysis using Pearson's Chi-squared test and multivariate analysis using the Cox proportional hazards regression model were performed to determine correlations between the development of grade two or more leukopenia and clinical factors. Results: Among patients with auto-PBSCT, grade two or more leukopenia occurred in five. The incidence of grade two or more leukopenia was significantly higher in patients with auto-PBSCT than in those without (p=0.014). Conclusion: Hematopoietic functions after auto-PBSCT may be more vulnerable to RT than normal hematopoietic functions.
- Autologous hematopoietic stem cell transplantation
- leukopenia
- thrombocytopenia
- high-dose chemotherapy
- myelosuppression
In recent years, high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) has been used for the treatment of relapsed Hodgkin's lymphoma (HL) and non-HL (1, 2). Large-scale phase III trials demonstrated the efficacy of ASCT after high-dose chemotherapy in patients with HL and non-HL. Thus, there is a consensus that high-dose chemotherapy followed by ASCT is a standard therapy for patients with chemosensitive disease (1, 3). Furthermore, radiation therapy (RT) is sometimes applied to sites of prior disease involvement after ASCT with the aim of preventing relapse of the disease (4, 5). However, studies of high-dose chemotherapy followed by ASCT vary with respect to the presence or absence of RT. Therefore, few studies have addressed the association between RT after ASCT and myelosuppression. Both bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are types of ASCT. PBSCT is safer and easier to use with engraftment compared to BMT, and it has been increasingly used worldwide. At present, PBSCT accounts for 99% of ASCT recipients (6). Here, we compared the incidence of myelosuppression after RT in patients with malignant lymphoma who underwent autologous PBSCT (auto-PBSCT) with that in patients who did not. To the best of our knowledge, this is the first study to examine the association of RT after auto-PBSCT with the development of myelosuppression.
Patients and Methods
In total, 20 patients with malignant lymphoma who received RT after chemotherapy from January 2012 to February 2018 were included in the analysis. This study was a retrospective study and patients not receiving RT after chemotherapy were excluded. Characteristics of patients who received RT are shown in Table I. Among them, six underwent auto-PBSCT. Most patients (15/20) had non-HL. BM involvement at the initial stage was documented in five patients by BM aspiration.
The first-line chemotherapy regimen consisted of cyclophosphamide, adriamycin, vincristine, and prednisone with/without rituximab in 14 patients; cyclophosphamide, vincristine, and prednisone with rituximab in one patient; and doxorubicin, bleomycin, vinblastine, and dacarbazine in five patients. The median number of chemotherapy regimens prior to RT was 2 (range=1-5). Almost none of the patients concomitantly received chemotherapy during the period of RT, and only one patient received cyclophosphamide hydrate tablet. The median time from completion of chemotherapy to the start of RT was 55 (range=4-1,287) days. Seven patients had a complete response (CR) at the time of RT, and 13 patients had a non-CR with residual disease in positron emission tomography/computed tomography (CT) or CT images. In all patients, the high-dose conditioning regimen followed by auto-PBSCT included high-dose cyclophosphamide, etoposide, and ranimustine (CEM) (7).
RT following auto-PBSCT was performed after engraftment was confirmed based on normalization of peripheral white blood cell and platelet counts. The median white blood cell count before RT was 4400 (range=3000-10700)/μI in patients after auto-PBSCT, and 3500 (range=1100-7800)/μI in patients without auto-PBSCT. The median platelet count before RT was 117 (range=48-232) ×103/μI in patients after auto-PBSCT, and 223 (range=53-331) ×103/μI in patients without auto-PBSCT. The median time from auto-PBSCT to the start of RT was 73 (range=29-605) days. The RT sites were the mediastinum in eight patients, pelvis in five, axilla and/or supraclavicle in two, abdomen in two, groin in one, and the whole brain and spine (simultaneous irradiation) in one. Parallel opposed anterior and posterior fields were used as the basic irradiation technique. The RT fields were involved nodes or the involved field at sites of prior disease involvement before chemotherapy or residual disease (8, 9). Because the RT sites of the patients differed, the RT field sizes were assessed using equivalent square fields and the median size was 11.4 (range=7.95-23.8) cm. The median RT dose was 30 (range=28.8-40) Gy. Peripheral white blood cell and platelet counts were measured up to 14 weeks after completion of RT. For patients with leukopenia or thrombocytopenia before or after RT, the development of grade ≥2 leukopenia and/or thrombocytopenia was examined according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 (10). This retrospective study was approved by the Institutional Review Board of Nihon University School of Medicine (approval number RK-180710-16) and the patients' written informed consent for all procedures was obtained.
Statistical methods. Univariate analysis using the Pearson's chi-squared test and multivariate analysis using the Cox proportional hazards regression model were conducted to determine the correlation between the development of grade two or more leukopenia or thrombocytopenia and the following factors: Histology (HL vs. non-NHL), initial clinical stage (I/II vs. III/IV), initial BM involvement (presence vs. absence), number of chemotherapy regimens prior to RT (1 vs. ≥2), auto-PBSCT (presence vs. absence), time from completion of chemotherapy to the start of RT (<55 or concomitant vs. ≥55 days), disease status at RT [complete response (CR) vs. non-CR], white blood cell count before RT (<3,750 vs. ≥3,750 μI), platelet count before RT (<184.5 vs. ≥184.5×103/μl), age at initiation of RT (<50 vs. ≥50 years), RT site (pelvis vs. non-pelvis), RT equivalent square field (<11.4 vs. ≥11.4 cm), and RT dose (<30 vs. ≥30 Gy). The Cox proportional hazards regression model was calculated by the time of nadir leukopenia or thrombocytopenia. SPSS ver. 21.0 (IBM, Armonk NY, USA) was used for statistical analysis.
Results
A comparison of myelosuppression toxicities after RT between patients who underwent auto-PBSCT and those who did not is shown in Table II. In patients who received RT after auto-PBSCT, grade 2 or more leukopenia occurred in five patients (grade 2 in one, grade 3 in three, and grade 4 in one) and grade 2 or more thrombocytopenia occurred in three patients (grade 3 in two and grade 4 in one). In patients who received RT, but did not undergo auto-PBSCT, grade 2 leukopenia occurred in four patients, but none experienced grade 2 or more thrombocytopenia. Univariate analysis showed that the incidences of grade 2 or more leukopenia and thrombocytopenia were significantly higher in patients who received RT after auto-PBSCT than in those who received RT but did not undergo auto-PBSCT (p=0.024 and p=0.004, respectively). Results of the multivariate analysis aimed at determining correlations between the examined factors and the development of grade 2 or more leukopenia and thrombocytopenia are shown in Table III. According to the Cox proportional hazards regression model, RT after auto-PBSCT significantly correlated with the development of grade 2 or more leukopenia (p=0.014). Neither univariate nor multivariate analyses showed any correlations between the development of grade 2 or more leukopenia or thrombocytopenia and variables such as the initial clinical stage, initial BM involvement, number of chemotherapy regimens, white blood cell and platelet counts before RT, RT site, RT equivalent square field, or RT dose. Furthermore, for patients who presented with grade 2 or more leukopenia and recovered from the condition, 255 and 164 days were required at the most for the white blood cell count to return to the normal level after completion of RT in patients who underwent auto-PBSCT and in those who did not, respectively. One patient experienced the longest period of myelosuppression, although it had taken 605 days from auto-PBSCT to the start of RT. Three out of six patients who underwent auto-PBSCT are disease-free to date.
Discussion
The relapse rate of patients with HL after the first combinatorial chemotherapy or RT is reportedly 25-43%, although it varies depending on the stage and risk factors (11). The reported CR rate of patients with non-NHL after the first combinatorial chemotherapy is 44-67%, although it also varies depending on the stage and risk factors (12, 13). A randomized study showed that patients who underwent PBSCT had better failure-free survival than those who underwent BMT (14). One of the advantages of high-dose chemotherapy followed by ASCT is its antitumor effect that results from the high-dose chemotherapy. Because the site of prior disease involvement before high-dose chemotherapy is at a high risk of relapse, several studies have suggested that additional RT to sites of prior disease involvement and residual disease may reduce the relapse risk (4, 15, 16). In contrast, few studies have evaluated toxicities caused by RT in addition to high-dose chemotherapy with ASCT. Thus, the optimal order of ASCT and RT has not yet been determined.
RT followed by ASCT is associated with a lower incidence of toxicities related to myelosuppression in relation to the irradiated field compared with RT after ASCT. In contrast, the incidence of pneumonitis and gastrointestinal toxicity is less with RT after ASCT than with RT followed by ASCT. Furthermore, when RT is performed after ASCT, high-dose chemotherapy would not be delayed, and the therapeutic effect of high-dose chemotherapy can reduce or increase RT doses (4, 17). For example, in patients who received RT after ASCT along with high-dose chemotherapy, stronger myelosuppression toxicity was associated with a more advanced initial clinical stage, but not with the RT dose or field size (18). In the above-mentioned study, the median time from high-dose chemotherapy to the start of RT was 140 days. Another study reported that grade 3 and 4 myelosuppression occurred in 16-21% of patients who received supradiaphragmatic involved-field RT after ASCT along with high-dose chemotherapy (17). In that study, the median time from ASCT to the start of RT was 56 days. In our study, the median time from auto-PBSCT to the start of RT was 73 days, which is between the time periods reported in previous studies. One study which evaluated myelosuppression in patients who received involved-field RT after ASCT along with high-dose chemotherapy reported that patients with malignant lymphoma were at a higher risk of developing myelosuppression than those with other solid tumor types, and that grade 4 myelosuppression occurred in 29% of patients (19). These studies involved only patients who received RT after ASCT along with high-dose chemotherapy.
To the best of our knowledge, the present study is the first to include patients who received RT but did not undergo auto-PBSCT as a control to examine the correlation between RT after auto-PBSCT and the development of myelosuppression. The incidence of grade 2 or more leukopenia was significantly higher in patients who received RT after auto-PBSCT than in those who received RT but did not undergo auto-PBSCT. The widely used regimens of high-dose chemotherapy include carmustine, etoposide, cytarabine, and melphalan as well as cyclophosphamide, carmustine, and etoposide (20). Our Institute uses the CEM regimen with outcomes similar to those of other regimens (7). Thus, the CEM regimen was used for all study patients who underwent auto-PBSCT.
In auto-PBSCT, the increased number of stem cells in the peripheral blood during hyperactive myelopoiesis after chemotherapy at usual doses are collected, cryoreserved, thawed after high-dose chemotherapy, and promptly infused to restore hematopoietic functions (21). In our patients who received RT after auto-PBSCT, RT was started after recovery of their hematopoietic functions was confirmed. Nevertheless, the incidence of myelosuppression in these patients was higher than in those who received RT, but did not undergo auto-PBSCT. One patient experienced the longest period of myelosuppression, although it had taken 605 days from auto-PBSCT to the start of RT. Hematopoietic functions after auto-PBSCT may be more vulnerable to RT than normal hematopoietic functions. RT fields and doses should be cautiously determined for patients who receive RT after auto-PBSCT considering the relapse risk factors because this is more likely to be associated with myelosuppression than RT without auto-PBSCT. An attempt to use intensity-modulated photon beams and proton beams has recently been made to reduce doses in bones within the irradiated field for the treatment of malignant lymphoma. Using these techniques, the reduced dose may result in a reduction in the incidence of myelosuppression (22). Thus, more cases of RT after auto-PBSCT must be assessed in order to evaluate the correlation between RT after auto-PBSCT and the development of myelosuppression using cases of RT without auto-PBSCT as a control.
Acknowledgements
The Authors thank Mitchell Arico from Edanz Group (www.edanzediting.com/ac) for editing a draft of this article and helping to draft the abstract.
Footnotes
Authors' Contributions
NI treated the patients and was a major contributor to writing the article. YU performed the chemotherapy. TM, MS, TA and MO took part in the treatment. MH analyzed the data. All authors read and approved the final article.
Conflicts of Interest
The Authors state that they have no conflicts of interest.
- Received February 6, 2019.
- Revision received February 27, 2019.
- Accepted March 13, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved