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  Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 57  |  Issue : 3  |  Page : 262-266
 

Outcomes of T-lymphoblastic lymphoma treated with pediatric ALL-like protocol


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 Submission17-Sep-2018
Date of Decision25-Oct-2018
Date of Acceptance26-Dec-2018
Date of Web Publication22-Jun-2020

Correspondence Address:
Hasmukh Jain
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_616_18

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 » Abstract 


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 article:
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 2020;57:262-6

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 [serial online] 2020 [cited 2020 Sep 20];57:262-6. Available from: http://www.indianjcancer.com/text.asp?2020/57/3/262/287381





 » Introduction Top


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.[1] 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.[2],[3] 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%.[4],[5],[6] Two studies from India reported overall survivals (OSs) of 44%–60% with various ALL-like regimens (with or without high dose methotrexate).[7],[8]

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.[9],[10]

As salvage following relapse is rarely achieved in either children or adults, it becomes imperative to identify poor responders early in treatment.[11],[12] 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.[2],[9] 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.[13]

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 Top


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.

Treatment

In total, 38 patients were treated using the pediatric BFM-90 protocol.[2] 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.

Statistical analysis

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 Top


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.
Table 1: Patient characteristics


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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.

Treatment response

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].
Table 2: Disease and treatment characteristics


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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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Toxicity

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 Top


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,[14] 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.[13] 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.[12]

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.[5],[6] 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.[15]

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.[11] 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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Schmidt E, Burkhardt B. Lymphoblastic lymphoma in childhood and adolescence. Pediatr Hematol Oncol 2013;30:484-508.  Back to cited text no. 1
    
2.
Reiter A, Schrappe M, Ludwig W-D, Tiemann M, Parwaresch R, Zimmermann M,et al. Intensive ALL-type therapy without local radiotherapy provides 90% event-free survival for children with T-lymphoblastic lymphoma: A BFM Group report. Blood 2000;95:416-21.  Back to cited text no. 2
    
3.
Burkhardt B, Woessmann W, Zimmermann M, Kontny U, Vormoor J, Doerffel W,et al. Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 2006;24:491-9.  Back to cited text no. 3
    
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Portell CA, Sweetenham JS. Adult lymphoblastic lymphoma. Cancer J 2012;18:432-8.  Back to cited text no. 4
    
5.
Marks DI, Paietta EM, Moorman AV, Richards SM, Buck G, DeWald G, et al. T-cell acute lymphoblastic leukemia in adults: Clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood 2009;114;5136-45.  Back to cited text no. 5
    
6.
Hoelzer D, Gökbuget N, Digel W, Faak T, Kneba M, Reutzel R, et al. Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood 2002;99:4379-85.  Back to cited text no. 6
    
7.
Sengar M, Akhade A, Nair R, Menon H, Shet T, Gujral S, et al. Aretrospective audit of clinicopathological attributes and treatment outcomes of adolescent and young adult non-Hodgkin lymphomas from a tertiary care center. Indian J Med Paediatr Oncol 2011;32:197-203.  Back to cited text no. 7
  [Full text]  
8.
Tilak TV, Raina V, Kumar L, Sharma A, Sharma MC, Vishnubhatla S, et al. Superior vena cava syndrome and poor performance status at presentation affect survival in mediastinal T-lymphoblastic lymphoma--a single institute experience from India. Ann Hematol 2013;92:917-23.  Back to cited text no. 8
    
9.
Grenzebach J, Schrappe M, Ludwig WD, et al. Favorable outcome for children and adolescents with T-cell lymphoblastic lymphoma with an intensive ALL-type therapy without local radiotherapy. Ann Hematol. 2001;80 Suppl 3:B73-B76.  Back to cited text no. 9
    
10.
Dabaja, BS, Ha CS, Thomas DA, Wilder RB, Gopal R, Cortes J, et al. The role of local radiotherapy for mediastinal disease in adults with T-cell lymphoblastic lymphoma. Cancer 2002;94:2738-44  Back to cited text no. 10
    
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Burkhardt B, Reiter A, Landmann E, Lang PJ, Lassay L, Dickerhoff R, et al. Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma – Report of the BFM Group. J Clin Oncol 2009;27:3363-9  Back to cited text no. 11
    
12.
Gökbuget N, Basara N, Baurmann H, Beck J, Brüggemann M, Diedrich H, et al. High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood 2011;118:3504-11.  Back to cited text no. 12
    
13.
Barrington SF, Mikhaeel NG. When should FDG-PET be used in the modern management of lymphoma? Br J Haematol 2014;164:315-28.  Back to cited text no. 13
    
14.
Burkhardt B. Paediatric lymphoblastic T-cell leukaemia and lymphoma: One or two diseases? Br J Haematol 2010;149:653-68  Back to cited text no. 14
    
15.
Hunault M, Truchan-Graczyk M, Caillot D, Harousseau JL, Bologna S, Himberlin C, et al. Outcome of adult T-lymphoblastic lymphoma after acute lymphoblastic leukaemia treatment: AGOELAMS trial. Haematologica 2007;92:1623-30.  Back to cited text no. 15
    


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