Annals of Oncology Advance Access originally published online on December 8, 2006
Annals of Oncology 2007 18(3):535-540; doi:10.1093/annonc/mdl426
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© 2006 European Society for Medical Oncology
hematologic malignancies |
Primary therapy for adults with T-cell lymphoblastic lymphoma with hematopoietic stem-cell transplantation results in favorable outcomes
The Leukemia/Bone Marrow Transplant Program of British Columbia, The Vancouver Hospital and Health Science Center, Divisions of Medical Oncology and Pathology, British Columbia Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada
* Correspondence to: Dr K. W. Song, Division of Hematology, Department of Medicine, Vancouver General Hospital, Jim Pattison Pavilion Room 3300, 950 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E3. Tel: +1 604-875-4863; Fax: +1 604-875-4763; E-mail: ksong{at}bccancer.bc.ca
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Abstract |
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Background: Controversy exists regarding the role of high-dose therapy followed by stem-cell transplant (SCT) in the treatment of T-cell lymphoblastic lymphoma (T-LBL). We conducted an intention-to-treat analysis of the strategy of SCT as definitive treatment of T-LBL.
Patients and methods: From July 1987 to March 2005, 34 adults with T-LBL were diagnosed and treated in British Columbia. Treatment, before planned SCT, consisted of a non-Hodgkin's lymphoma (NHL)/acute lymphoblastic leukemia hybrid chemotherapy protocol (28 patients) or a standard NHL chemotherapy regimen (six patients).
Results: Median follow-up of the 23 surviving patients is 51 months (range 13–142 months). Twenty-nine proceeded to SCT (four allogeneic, 25 autologous). For all 34 patients, 4-year overall survival (OS) and event-free survival (EFS) are 72% and 68%, respectively. For patients proceeding to SCT, the 4-year OS and EFS are 79% and 73%, respectively. All patients who received allografts are alive without disease at 38–141 months since diagnosis. For patients who received autografts, the 4-year EFS is 69%. Bone marrow involvement was a significant prognostic factor predicting for a worse survival (P = 0.02).
Conclusion: A treatment strategy for adults with chemosensitive T-LBL that includes planned consolidation with SCT in first response produces favorable long-term outcome.
Key words: acute lymphoblastic leukemia, lymphoblastic lymphoma, stem-cell transplant, T-cell lymphoma
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introduction |
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Lymphoblastic lymphoma (LBL) is an uncommon malignancy accounting for <2% of non-Hodgkin's lymphoma (NHL) [1]. Most commonly, it is of T-cell immunophenotype with
20% being B cell. In the World Health Organization classification, LBL is considered a precursor B-cell/T-cell neoplasm and thought to be the nodal/extranodal presentation of acute lymphoblastic leukemia (ALL) [2]. Arbitrarily, 25% bone marrow involvement has been considered the cut-off in differentiating between LBL and ALL. In adults, it is most commonly diagnosed in young males, typically presenting with a mediastinal mass. Treatment with standard lymphoma chemotherapy protocols has resulted in poor long-term, disease-free survival [3]. It is now believed that ALL chemotherapy regimens are more appropriate for LBL. In the pediatric population, ALL chemotherapy has produced excellent results with the majority of the children being cured [4, 5]. More recent data have demonstrated less impressive but nonetheless good results in adults [6, 7]. Because of the high risk of relapse, high-dose chemotherapy followed by hematopoietic stem-cell rescue [stem-cell transplant (SCT)] has also been used to consolidate remission [8–10]. It remains uncertain if SCT leads to improved survival although there is evidence supportive of such an approach with higher disease-free survival rates being reported [11]. Difficulty in appreciating the role of SCT in the treatment of LBL is compounded by the rarity of this condition and the selection/referral biases encountered in transplant studies. In British Columbia (BC), since 1987, all patients with LBL have been treated with planned combination chemotherapy, to be followed by consolidation with high-dose chemotherapy followed by stem-cell rescue (SCT). This study reports on the results of this treatment policy in an intention-to-treat analysis. |
patients and methods |
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study group
The Research Ethics Board of the University of BC gave approval for retrospective review and analysis of all patients diagnosed with LBL. All patients gave informed consent for treatment. Adult patients with T-cell lymphoblastic lymphoma (T-LBL) presenting in BC were identified by searching the established databases from The Leukemia/Bone Marrow Transplant (BMT) Program of BC and Lymphoid Cancer Database of the British Columbia Cancer Agency (BCCA). In order to avoid referral bias, patients referred from outside of BC were excluded. Patients with human immunodeficiency virus (HIV) infection were also excluded. Only patients between the ages of 16 and 65 at the time of diagnosis were included in order to determine the outcome of transplant-eligible adult patients.
diagnosis
The diagnosis was established by histological examination of the tissue biopsy and establishment of T-cell origin on the basis of flow cytometric analysis and/or immunohistochemistry. Patients with >25% bone marrow involvement or 5% lymphoma cells in the peripheral blood were excluded to avoid inclusion of patients with ALL. Patients with B-cell LBL (n = 5) were excluded because of its rarity and the uncertain prognostic significance of the immunophenotype. All diagnostic specimens were centrally reviewed at the BCCA by dedicated hematopathologists (RDG and MC).
initial assessment
Staging evaluations included computed tomography (CT) of the abdomen and pelvis, CT or X-ray of the chest; bone marrow aspiration and trephine biopsy; a biochemical profile including creatinine clearance, aspartate aminotranferase, alanine aminotransferase, bilirubin and lactate dehydrogenase (LDH) and cerebrospinal fluid sampling for cytology and cell count. Clinical staging was based on the Ann Arbor Classification [12]. Limited stage was defined as those with stage I–II nonbulky (<10 cm greatest diameter) disease. Charts were reviewed retrospectively to collect clinical data regarding presentation, treatment and outcome.
induction therapy
Before 1998, patients were treated initially with one of several standard chemotherapy regimens for aggressive histology lymphoma to establish control over the disease and to document chemosensitivity. Since 1998, patients have been treated with an induction chemotherapy protocol developed specifically for LBL, which combines features of NHL and ALL treatment (Table 1). A feature of the protocol is the dose intensity in the first week of the treatment. Patients are assessed for response 4 weeks after initiation of chemotherapy. Patients demonstrating chemosensitive disease with a partial response (PR) or better are considered eligible for SCT. A central part of the treatment strategy for all 34 patients included in this study was to proceed to SCT as soon as possible to avoid the risk of progression. All patients were given 5–10 doses of intrathecal cytarabine 50 mg and/or methotrexate 12–15 mg throughout the course of the treatment.
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high-dose therapy
All patients were considered for autologous stem-cell transplantation (autoSCT); however, selected patients were considered for allogeneic stem-cell transplantation (alloSCT) if a matched sibling was available. Reasons for considering alloSCT in preference to an autoSCT included younger age and bone marrow involvement with lymphoma. Pretransplant work-up was carried out to ensure adequate organ function. Every effort was made to use total body irradiation (TBI) as a part of the conditioning regimen.
source of hematopoietic stem cells
For autologous stem cells, during the period of this study, practice changed from the use of bone marrow to peripheral blood stem cells. Ex vivo purging was carried out until 2004 when mafosphamide became no longer available. None of the peripheral blood stem cells units were purged. Allogeneic stem cells were initially collected from the bone marrow, but practice also changed to the collection of peripheral blood stem cells. Allogeneic stem cells were not manipulated.
response criteria
Complete remission (CR) was defined as complete disappearance of all previously detectable clinical, radiological and histological/immunophenotypic evidence of the disease. PR was defined as >50% reduction in the sums of the products of the biperpendicular diameters of all measurable disease. No response was defined as <50% reduction in the sums of the products of the biperpendicular diameters of all measurable disease. Progressive disease was defined as >25% increase in the size of previously documented disease or the appearance of disease at new sites. There was no predefined duration of response required as the strategy was to proceed to SCT as soon as possible.
supportive care
All patients were hospitalized in HEPA-filtered rooms for the conditioning regimen and transplantation procedure. Infection prophylaxis included aciclovir, trimethoprim sulfamethoxazole/pentamidine for Pneumocystis carinii prophylaxis and fluconazole/low-dose amphotericin for fungal prophylaxis. Low-dose heparin was used for veno-occlusive disease prophylaxis. All blood products were irradiated. Cyclosporine and short-course methotrexate was used for graft-versus-host disease (GVHD) prophylaxis for those undergoing alloSCT.
statistical analysis
Unless stated otherwise, all survival analyses were calculated from the time of diagnosis. Median time from diagnosis to SCT was only 2.2 months (range 1.3–6.5 months) which allowed the use of date of diagnosis as the reference time for survival. Event-free survival (EFS) duration was calculated from the time of diagnosis until relapse, disease progression, death from any cause or until last follow-up if none of these events had occurred. Overall survival (OS) duration was calculated from the date of diagnosis until death from any cause or until last follow-up for surviving patients. Surviving patients were censored at the last date on which they were known to be alive for OS and alive without relapse or progression for EFS. Estimated OS and EFS rates were calculated using the product-limit method of Kaplan–Meier and compared using the log-rank test [13]. All P values are two-sided and P <0.05 was considered statistically significant.
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results |
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characteristics
From July 1987 to March 2005, 38 adult patients presenting with T-LBL in BC were identified. Four patients were excluded because of bone marrow involvement >25% and are not included in any of the following descriptions or analysis. None of the patients were referred from outside of BC and none had HIV. The remaining 34 patients were treated by the leukemia/BMT Program of BC. Follow-up data were collected until June 2006 to ensure minimum 1-year follow-up. Characteristics at presentation are listed in Table 2. Median age at diagnosis was 26 years (18–56 years). Most patients had advanced disease with seven patients (21%) having bone marrow involvement and 19 (56%) an elevated LDH at diagnosis. Median white blood cell count at diagnosis was 8.2 x 109/l (range 1.5–21) and platelet count 288 x 109/l (range 137–492).
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initial chemotherapy
Nineteen patients were treated with NHL 98-01, the uniform protocol adopted in 1998 (Table 1). Nine patients diagnosed before 1998 were treated with other ALL/NHL hybrid regimens similar to NHL 98-01 and six patients were treated with combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone-like regimens. All patients had chemosensitive disease, achieving at least a PR. Median follow-up of the 23 surviving patients is 51 months (range 13–142 months). OS and EFS at 4 years for all patients are 72% [95% confidence interval (CI) 56% to 88%] and 68% (95% CI 52% to 85%), respectively (Figures 1 and 2).
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stem-cell transplantation
Five patients did not proceed to SCT in first response. Reasons for not proceeding to SCT included patient refusal (n = 1); decision to offer SCT only at the time of relapse (n = 2); poor patient compliance (n = 1) and poor organ function (n = 1). One of these five patients relapsed by 1 year following initial diagnosis, responded to salvage chemotherapy and then proceeded to autoSCT in CR2. He relapsed again shortly afterwards and died within 2 years of initial diagnosis. Only one patient who did not undergo SCT remains alive without disease, now 10 years since diagnosis.
Twenty-nine patients proceeded to SCT in first response. Nineteen patients had achieved a CR/CRu and 10 achieved a PR with induction chemotherapy. Conditioning regimens used are listed in Table 3. Median follow-up of the 22 surviving patients who underwent SCT is 51 months (range 13–142 months). The OS and EFS at 4 years for these patients are 79% (95% CI 63% to 94%) and 73% (95% CI 56% to 91%), respectively (Figures 1 and 2). Four patients (one with bone marrow involvement) underwent matched sibling alloSCT. All four received TBI as a part of the conditioning regimen. Stem-cell source was bone marrow for two and peripheral blood for the other two. Two patients developed both acute and chronic GVHD, one developed only acute GVHD and the remaining patient developed only chronic GVHD. All remain alive without disease and with normal performance status, 38–141 months since initial diagnosis. The remaining patients received autoSCT. All patients received TBI except two for whom there were concerns of pulmonary toxicity. Consolidative radiation specific to the mediastinum was not given. Stem-cell source was purged bone marrow for 16 (4-hydro-peroxycyclophosphamide for one patient and mafosfamide for 15 patients), unpurged peripheral blood for seven, unpurged bone marrow for one and combined unpurged peripheral blood and bone marrow for one. For the 25 patients undergoing autoSCT, the 4-year EFS was 69%.
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prognostic factors
Analysis for prognostic factors was carried out only for the 29 patients who proceeded to SCT in first response. In univariate analysis, the only significant factor predicting for an inferior EFS and OS was the presence of disease in the bone marrow (P = 0.02 and P = 0.02, respectively) (Figure 3). Nonsignificant factors included gender, increased LDH, presence of a mediastinal mass, presence of a pleural/pericardial effusion, age-adjusted International Prognostic Index (IPI) score [14] and CR versus PR at the time of SCT. The small number of patients with disease in the cerebrospinal fluid (n = 1) or blood (n = 2) did not allow for assessment of their prognostic value. For those who underwent autoSCT, there was no significant difference between those who received bone marrow compared with peripheral blood stem cells. Those who received purged autologous stem cells had a significantly superior EFS (P = 0.03), although OS was not significantly improved (P = 0.10).
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treatment failures
One patient died of interstitial pneumonia 3 months after transplantation. Six patients relapsed at 2, 4, 4, 10, 11 and 40 months after the transplant. All died within 6 months of relapse. Three patients relapsed in the mediastinum with one of these patients relapsing in the bone marrow as well. The remaining three patients relapsed predominantly in the bone marrow. Three of the six patients who relapsed did not have bone marrow involvement at initial diagnosis. At this time, no patient has developed therapy-related myelodysplastic syndrome or acute leukemia.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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This study describes a population-based treatment policy of treating adults diagnosed with T-LBL with SCT as the definitive part of the curative strategy. The centralized treatment policy in BC has allowed for the capturing of all patients diagnosed and treated in this province, resulting in a thorough assessment of characteristic at diagnosis and an intention-to-treat analysis of the treatment strategy. Similar to previous studies, T-LBL was found most commonly in young males. A mediastinal mass was present in
80% of the patients with 60% having a pleural and/or pericardial effusion. Adequate long-term follow-up has demonstrated favorable results with the strategy of treating patients diagnosed with T-LBL with a hybrid NHL/ALL chemotherapy protocol followed by high-dose chemotherapy with stem-cell rescue. For all 34 patients, the 4-year EFS was 68%, and for patients who proceeded to SCT in first response, the 4-year EFS was 73%. Not surprisingly, those with bone marrow involvement were found to have worse outcomes. Interestingly, advanced-stage and increased-risk IPI did not predict for a worse outcome. Although those who received purged autologous bone marrow had significantly improved EFS, caution is required in interpreting this result since the follow-up of patients who received unpurged autologous stem cells is relatively short (the policy was changed in 2004). Our results support the rationale of using SCT to consolidate a first remission in patients diagnosed with T-LBL; however, chemotherapy alone has also produced impressive results. The German Multicenter Study Group for adult ALL (GMALL) published their series of 45 patients who were treated with an ALL protocol resulting in a disease-free survival at 7 years, which was 51% [7]. Investigators at MD Anderson have also reported that a progression-free survival of 66% can be achieved with hyper-CVAD [6]. These reports indicate that intensive chemotherapy is required to achieve good results if SCT is not pursued. Further intensification of the chemotherapy that the five patients who did not undergo SCT received may have improved their poor outcome. A randomized study comparing chemotherapy alone with chemotherapy consolidated with autoSCT was initiated to try to define the role of SCT in the treatment of LBL [15]. Unfortunately, the trial had to be terminated because of poor accrual. This trial demonstrated a nonsignificant trend towards improved survival in patients who received an autoSCT compared with those treated with chemotherapy alone with the 3-year relapse-free survival being 55% compared with 24% [15]. It is uncertain if a larger sample size would have resulted in a statistically significant result. The difference in OS was even less apparent, but a number of patients in whom chemotherapy failed eventually proceeded to SCT in second response and achieved a durable remission.
The role of radiation as a part of the treatment of T-LBL may be important for improving relapse-free survival. The GMALL administered prophylactic mediastinal radiation as part of their treatment program [7]. A French study examined the results of 25 patients who underwent SCT in first response (12 autoSCT, 13 alloSCT) using radiation as a part of the conditioning for all patients [16]. The actuarial disease-free survival at 4 years was 68%. This impressive result may have been due to the assignment of many patients to an alloSCT, but it is also possible that the radiation had a significant influence on disease control. In our study, all patients received radiation as a part of the SCT-conditioning regimen, except for two in whom radiation was contraindicated. One of these two patients relapsed in the mediastinum and bone marrow and died. Two other patients relapsed in the mediastinum. The addition of consolidative radiation to the mediastinum after SCT may be a possible strategy to improve outcome, but any gain may be offset by added toxicity.
Our study includes a small number of patients who received alloSCT with the majority receiving autoSCT. Registry data indicate that results with both types of SCT are similar. For those who undergo alloSCT, the decreased risk of relapse is counterbalanced with the increased treatment-related mortality [17]. For this reason, the younger patients at high risk of relapse (such as those with bone marrow involvement) with a histocompatible sibling may derive more benefit from an alloSCT.
There are several potential drawbacks with our treatment strategy. Stem-cell transplantation is difficult to tolerate, but in this group of patients with a median age of 26 at diagnosis, only one patient had a fatal outcome from treatment. Fertility is a major issue with all patients becoming infertile with radiation-based conditioning regimen, although for males, sperm banking is an option. Secondary hematological malignancies are also a concern [18]. Even considering these potentially undesirable outcomes, however, in this population of young adults, these disadvantages are outweighed by the favorable results of the current treatment strategy.
In conclusion, this population-based study demonstrates favorable outcomes in adults with T-LBL who are treated with a hybrid NHL/ALL chemotherapy protocol followed by consolidation with SCT. This treatment can be easily carried out and fully completed within 6 months of diagnosis. Results of this strategy appear superior to the use of chemotherapy alone. Planned SCT is a reasonable treatment option for newly diagnosed adult patients with T-LBL and can be expected to cure the majority of patients.
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Acknowledgements |
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The authors thank Alan Le, Janet Nitta and Nancy Roth for assistance with data analysis and management and the nursing and medical staff on Tower 15A ward and the Leukemia/BMT Medical Daycare at the Vancouver Hospital and Health Sciences Centre and 6 West ward of the BC Cancer Agency for patient care. This paper was presented in part at the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 2004.
Received for publication August 14, 2006. Revision received October 14, 2006. Accepted for publication October 16, 2006.
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