|Ahead of print
Outcomes of T-lymphoblastic lymphoma treated with pediatric ALL-like protocol
Manju Sengar1, Robert Carr2, Hasmukh Jain1, Raajit Chanana1, Venkatesh Rangarajan3, Epari Sridhar4, Tanuja Shet4, Hari Menon1, Sumeet Gujral4, Siddhartha Laskar5
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Haematology, Guy's and St Thomas' Hospital, King's College, London, UK
3 Department of Nuclear Medicine, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
5 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Submission||17-Sep-2018|
|Date of Decision||25-Oct-2018|
|Date of Acceptance||26-Dec-2018|
|Date of Web Publication||22-Jun-2020|
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: The management of T-lymphoblastic lymphoma (T-LBL) in adults poses uncertainties, including optimal chemotherapy regimen, need for radiotherapy, and the benefit of stem cell transplant. This retrospective case series investigated the efficacy of the pediatric BFM-90 regimen in adult patients and evaluated the role of early response assessment by positron emission tomography with computed tomography (PET-CT) in predicting outcomes.
Methods: Patients aged 15 years or older with T-LBL diagnosed at Tata Memorial Hospital, Mumbai, India were given chemotherapy according to the European BFM-90 protocol (n = 38). The patients were evaluated for early response by interim PET-CT, post-induction and monitored for toxicity and long-term outcomes.
Results: Thirty-eight consecutive patients (median age 23.5 years) were analyzed. After a median follow-up of 33.5 (1–77) months, following induction, 35 out of 38 patients (92.1%) had achieved complete response (CR) on PET-CT. Thirty (78.9%) patients treated according to BFM-90 were alive in first remission. Three-year event-free survival for those with CR on PET-CT was 78%, against no survivors for those who remained PET-positive.
Conclusion: This study demonstrates the feasibility and efficacy of BFM-90 approach in adults with T-LBL. We found an early PET response to be highly predictive of outcome.
Keywords: BFM-90, outcomes, PET response, T-LBL
|How to cite this URL:|
Sengar M, Carr R, Jain H, Chanana R, Rangarajan V, Sridhar E, Shet T, Menon H, Gujral S, Laskar S. Outcomes of T-lymphoblastic lymphoma treated with pediatric ALL-like protocol. Indian J Cancer [Epub ahead of print] [cited 2020 Jul 5]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=287381
| » Introduction|| |
Lymphoblastic lymphoma (LBL) is an uncommon tumor comprising 2% of all non-Hodgkin Lymphomas (NHL). The most common T-cell variant, T-lymphoblastic lymphoma (T-LBL), presents as a mediastinal thymic mass, occurring mainly in children, adolescents, and young adults. In Europe, children with T-LBL are most frequently treated with an intensive acute lymphoblastic leukemia (ALL) type regimen, which includes early use of asparaginase, high dose methotrexate, but not mediastinal radiotherapy, and maintenance upto 2 years from diagnosis, developed as the BFM-90 protocol., The initial study reported an estimated 5-year event-free survival (EFS) of 90% in childhood LBL. In Europe, adults with T-LBL are generally treated with adult ALL regimens, either with or without a consolidation stem cell transplant and are reported to have inferior outcomes, with long-term survivals of between 50% and 60%.,, Two studies from India reported overall survivals (OSs) of 44%–60% with various ALL-like regimens (with or without high dose methotrexate).,
In T-LBL, treatment failures usually occur within a year of starting treatment, the mediastinum being the most common site. Pediatric studies have found omission of radiation as part of the standard protocol not to increase relapse, whereas in adults' consolidative mediastinal radiotherapy is reported to decrease relapse.,
As salvage following relapse is rarely achieved in either children or adults, it becomes imperative to identify poor responders early in treatment., In children, a residual thymic mass on computed tomography (CT) at the end of induction is associated with increased relapses but does not always indicate residual disease; a pediatric T-LBL study found only necrotic tissue when residual masses were resected post-induction., Functional imaging combining CT with18 FDG-positron emission tomography (PET-CT) might be more sensitive to detect residual viable tumor, differentiate cases with faster or slower response to chemotherapy, and have prognostic impact as reported for Hodgkin's lymphoma and diffuse large B-cell lymphoma.
The hemato-oncologists at Tata Memorial Hospital (TMH), Mumbai initiated a treatment program for T-LBL in adults, according to the BFM-90 pediatric protocol, and assessing early treatment response by PET-CT. We report the treatment outcomes and the possible role of early PET-CT of these cohorts.
| » Methods|| |
This retrospective analysis includes all patients with newly diagnosed T-LBL aged >15 years, treated at TMH, Mumbai, India between January 2010 and December 2014. The start dates represent the time that the BFM-90 approach was introduced.
Diagnosis and staging
Diagnosis was according to standard histology and immunohistochemistry. The diagnosis of T-LBL needed blastoid morphology with immunoreactivity for Terminal deoxynucleotidyl transferase (TdT) and CD3. Where cases were negative for CD3, immunoreactivity with other T-cell markers (CD5, CD7) along with absence of B-cell markers (CD20 and Pax-5) was required for diagnosis. Pre-treatment staging was by PET-CT, or by CT alone in cases where patients could not tolerate the longer PET-CT scanning time.
In total, 38 patients were treated using the pediatric BFM-90 protocol. The dose of methotrexate was modified to 3.5g/m2. Following a 7-day prednisolone pre-phase, phase I chemotherapy “induction” comprises four drugs delivered over 4 weeks (prednisolone, vincristine, daunorubicin, and asparaginase), followed by phase II “consolidation” of cyclophosphamide and cytarabine over 4 weeks; then high-dose methotrexate, 4 doses at 2 week intervals; a truncated re-induction and consolidation over 6 weeks, followed by maintenance with oral mercaptopurine and methotrexate for 2-years from start. Cranial radiation of 12 Gy was given along with intrathecal methotrexate for cranial prophylaxis.
PET-CT and response assessment
Patients were scanned by PET-CT for early treatment response at the end of the phase I induction or, in 10 cases, following phase II consolidation of BFM-90 protocol. At TMH,18 F-FDG (5 MBq per Kg) is injected, with 60-min uptake, and scanned on a general electric (GE) discovery ST PET/16 slice CT scanner. Scans are reported using Deauville criteria, with additional information from SUVmax. A Deauville score of ≤3 was considered to be a complete response (CR).
Research ethics and data protection
Patient data were extracted from case records by the clinician responsible for the patients' treatment and was fully anonymized prior to analysis. The study was approved for publication by the Institutional Review Board.
EFS was calculated from diagnosis to date of progression, death, relapse from CR or date and disease status at last follow-up. OS was calculated from diagnosis to death from any cause or date of last follow-up in CR. Patients with progressive disease not suitable for further treatment were censored at date last known to be alive, if date of death was not known. The Kaplan-Meier method was used for calculation of EFS and OS. The Log-rank test was done to evaluate the effect of early PET-CT response on EFS and OS.
| » Results|| |
Patients and treatment
A total of 38 patients with T-LBL were identified for inclusion. Thirty-four patients (89.4%) presented with a bulky mediastinal mass; Twenty-four (63.2%) had stage IV disease with pleural/pericardial involvement, or other extranodal disease. Patient characteristics are shown in [Table 1]. The patients were aged from 15 to 44 (median, 23.5) years. Thirty-three (86.8%) patients were male.
Pre-steroid PET-CT was possible in 23 patients. Remaining patients underwent baseline CT scan. Orthopnea secondary to superior vena cava obstruction and/or massive pleural effusion was a common presentation in T-LBL and prevented baseline PET-CT in these patients. Three patients received a prolonged steroid pre-phase for up to 4 weeks prior to chemotherapy. All other cases received chemotherapy according to protocol.
At the time of analysis, with a median follow-up of 33.5 months, the number alive in first complete remission was 78.9% (30) for those treated on the BFM-90 protocol. As assessed by PET-CT for early response, 92.1% (35) had achieved a complete response when scanned. The Deauville score distribution of interim scan done has been described in [Table 2]. Three patients with persistent abnormal fluorodeoxyglucose (FDG) uptake at primary disease sites on this scan, received mediastinal radiotherapy. Two patients died after 7 months and one died after 22 months. Three patients relapsed after the early-response PET-CT showed complete remission. Notably, all 3 patients had received prolonged steroid therapy (>10 days) prior to cytotoxic chemotherapy. Disease and treatment characteristics are summarized in [Table 2]. The median follow-up period was 33.5 months. The 3-year EFS was 78% (P < 0.001) [Figure 1]. Three-year OS was 78% compared to no survivors with residual abnormal FDG uptake (P < 0.001) [Figure 2].
|Figure 1: Event-free survival (EFS) of all patients treated with BFM-90, n = 38|
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|Figure 2: Overall survival (OS) of all patients treated with BFM = 90, n = 38|
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Neutropenia following the primary induction, consolidation and the re-induction and consolidation phase was, in some patients, prolonged and contributed to infection-related death in remission of three cases.
| » Discussion|| |
This study demonstrates that a complete metabolic response after primary induction for T-LBL is highly predictive of cure, whereas patients with residual FDG-avid disease on PET-CT at the end of induction have a dismal outcome. In the absence of other clinical or biological markers, speed of response as assessed by PET-CT appears to be a promising early indicator of long-term outcome.
Compared to the many PET-response studies in B-NHL, there is less data on PET in T cell lymphomas. These data suggest that patients with a residual PET-positive mediastinal mass post-induction have such a poor prognosis that they should be considered for early treatment intensification using radiotherapy and/or nelarabine and stem cell transplant.
The study found that an intensive, pediatric ALL-like regimen with high-dose methotrexate could be delivered to adults up to mid-40 with similar high rates of cure, without the use of radiotherapy or transplant. The 3-year overall and disease-free survivals compare favorably with more traditional treatment approaches using adult ALL chemotherapy regimens in Europe or India., The survival of our cases treated on BFM-90 is at least as good as adults treated more intensively with a consolidation autologous stem cell transplant.
Our outcomes, while better than treatment approaches more commonly used in adults, confirm that disease progression mostly occurs within 12 months from start of treatment, and that salvage therapy is rarely effective. Similar to trials which have used pediatric leukemia regimens in young adults with ALL, our case series has likewise shown greater toxicity than reported in children with T-LBL on the BFM-90 regimen. However, this appears offset by increased efficacy.
We acknowledge that this is preliminary data with several limitations. There was variation with the timing of the treatment-response scans, and not all cases were able to have pre-treatment PET scans for reasons of clinical safety, though our experience is that T-LBL is consistently and intensely FDG-avid.
Nonetheless, from the results of the study we can conclude: (i) the BFM-90 regimen is similarly as effective in adults as in children, suggesting consistent disease biology, irrespective of age; (ii) the speed of treatment response monitored by an early interim PET-CT is highly indicative of outcome; and (iii) a prolonged course of steroids prior to chemotherapy increases relapse rate, irrespective of response to induction chemotherapy.
We propose that PET-CT monitoring should be introduced into T-LBL management, though our retrospective report needs validation by prospective studies. We also suggest that the BFM-90 approach to treatment should be systematically investigated in young adults upto 40 years, to cover the full age range where the disease is common, to define efficacy and toxicity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]