Treatment outcomes of adult acute lymphoblastic leukaemia in Auckland, New Zealand
View Article PDF
Introduction
Acute lymphoblastic leukaemia (ALL) is a neoplasm of immature lymphoid cells. The estimated incidence world-wide in 2017 was 0.85 per 100,000.[[1]] It is classically divided into T- and B-cell lineages. Presenting features include cytopenias, lymphadenopathy and organ infiltration.
The treatment of ALL involves multi-agent chemotherapy. An initial intensive phase lasts 6 to 9 months, with a subsequent maintenance phase lasting for up to 2 years. The goal is to achieve a measurable residual disease (MRD) negative status, where leukaemic cells are unable to be detected using current techniques; this is associated with superior outcomes.[[2,3]] Allogeneic stem cell transplantation (allo-SCT) is recommended in those who do not attain an MRD-negative state or who have high-risk genetics.[[4]]
Outcomes in children are excellent, with a 5-year overall survival (OS) exceeding 90%.[[5]] However, the OS in adults historically ranges from 5 to 55%.[[2,6,7]] This may be due to a) treatment with less intensive regimens due to risk of adverse events, b) comorbidities, c) higher incidence of high-risk genetics, d) treatment delays due to toxicity, and e) comparative lack of ancillary services and support in older patients. Adolescents and young adults (AYA), which is defined as age from 10 up to 39, is a unique sub-group. These patients (and potentially patients up to 45 years old) when treated with paediatric protocols do better compared with adult protocols, with one review finding a relative risk of 0.55 for all-cause mortality at 3 years favouring paediatric regimens.[[8]] In the very high-risk category of patients (which includes all patients aged between 13 and 30) treated on the COG1131 trial, the 4-year disease-free survival was 76%.[[9]] New Zealand data from between 2008 and 2017 found that the 5-year survival in the 15–24-year-old cohort improved from 68% to 79% overall. However, survival in Māori/Pacific Islanders remain lower than non-Māori/Pacific Islanders, with the 5-year survival being 75%, 73% and 82% respectively.[[10]]
In the Northern region all patients aged 16 and over who are candidates for curative therapy are referred to the adult haematology department at Auckland City Hospital (ACH). From 2018, all AYA ALL patients in the former Waikato District Health Board (DHB) were referred, and from early 2019 all AYA patients in MidCentral DHB were also referred in to ACH. AYA patients aged between 16 and 30 are treated using Children’s Oncology Group (COG) protocols within a trial or on the control arm of the most recent trial. Adults aged from 31 up to 60 are treated using the control arm of the UKALL14 protocol; the UKALL14 is the latest adult ALL trial from the UK.[[11]] Adults aged above 60 are treated using CALGB8811 (called CALGB60+) or UKALL60+ protocols based on fitness; these regimens are less intensive compared to the UKALL14.[[12,13]] The CALGB60+ is of an intermediate intensity between the UKALL protocols, while the UKALL60+ is of lower intensity and does not contain asparaginase. The protocols are adapted based on funded drugs. Allo-SCTs were carried out according to protocols if a donor could be identified.
The aim of this audit was therefore to review the characteristics and outcomes of ALL patients treated by the adult haematology service at ACH between 2016 and 2021.
Methods
Study design and data sources
This was an audit conducted by the adult haematology department at ACH. Data including patient details and selected clinical outcomes was collected prospectively for all de novo patients referred to ACH with confirmed ALL, biphenotypic acute leukaemia that included a lymphoid lineage, or CML in lymphoid blast crisis from June 2016. If the diagnostic bone marrow biopsy found <25% morphologic blasts, this was considered a B- or T-lymphoblastic lymphoma (LLy). We then retrospectively collected additional data from electronic hospital records, including demographics and other specific outcomes such as adverse events and treatment delay, into the database. This was anonymised, password protected and then analysed. Community records were not accessed as essentially all relevant care was conducted by the department. Institutional and ethical approval was sought from the Auckland City Hospital Research Office but was deemed to be not required.
Inclusion criteria
Patients in the database from 1 June 2016 to 1 November 2021 were included in this analysis. Patients who commenced therapy overseas but were transferred to ACH after induction were also included.
Exclusion criteria
Patients who were referred to ACH purely for allo-SCT and those predominantly treated overseas were excluded.
Definitions
The diagnosis of ALL was based on the consensus opinion of the Auckland acute leukaemia multi-disciplinary meeting. The date of diagnosis was based on the date of the first bone marrow biopsy.
Event-free survival (EFS) was defined as the time from diagnosis until a relapse or primary refractory state was diagnosed on a bone marrow or peripheral blood specimen, or death.
Complete remission was defined as <5% leukaemic blasts on a bone marrow biopsy. MRD was determined by flow cytometry (for B-ALL, COG standard (3 tube, 6 colour panel) and leukaemia-specific phenotype for T-ALL) for the purposes of this audit; a negative state was defined as <0.01%.
If a patient died after a diagnosis of relapsed or refractory disease, then this was considered the cause of death. Otherwise, deaths were defined as treatment related—for example, sepsis or liver failure. If the patient died of an unrelated cause, this was considered treatment unrelated.
The COG category included all patients treated with on a COG protocol, 1131 and 1732 for B-ALL and 1231 for T-ALL. The 60+ category included those treated with CALGB60+ and UKALL60+. The UKALL14 category is standalone. A few patients were treated with other protocols, and were included in the survival analysis but not displayed on selected KM curves due to the small numbers.
For the analysis of treatment delays, the minimum days in each phase of treatment was subtracted from the actual days.
Statistical analysis
A statistician (RH) was employed to perform statistical analysis using the SAS 9.4 programme. The Log-Rank test was used to determine statistical significance via Kaplan–Meier (KM) curves for differences in outcome. Other analytical methods are presented with the relevant results below. All confidence intervals (CI) displayed are of 95% percentile.
Results
A total of 65 patients were included in this audit. There were 52 B-ALL and 13 T-ALL patients. Table 1 summarises the demographic data.
View Table 1–4 and Figures 1–4.
Overall, 27 patients (41%) died during the study period. Of these, five (19%) were due to primary refractory disease, 14 (52%) were due to relapse, and seven (26%) due to treatment related mortality. One patient relapsed but died of a treatment unrelated ruptured aortic aneurysm.
The median OS was 37.6 months, 37 months, and not reached (NR) for all patients, B-ALL and T-ALL respectively. The median PFS was 30.2 months for B-ALL, and NR for T-ALL. The 3-year OS and EFS was 51% (standard error [SE)] 0.07) and 50% (SE 0.07) for all comers, 47% (SE 0.09) and 45% (SE 0.09) for B-ALL, and 62% (SE 0.13) and 62% (SE 0.13) for T-ALL respectively. Figure 1 displays the KM curves for OS and EFS.
When classified by protocol, the median OS and 3-year OS was 27.5 months (confidence interval [CI] 9.8–42.0) and 19% (SE 0.16) for 60+; 37.6 months (CI 11.7–37.6) and 53% (SE 0.11) for UKALL14. The median OS was not reached for COG, but the 3-year OS was 72% (SE 0.11). Figure 2 displays the KM curve.
Figure 3 displays the outcomes for B-ALL only, and demonstrates the effect of age and treatment protocol on outcomes. Table 2 shows the 3-year survival outcomes. Despite the small numbers, patients treated with COG have a statistically superior EFS with a HR of 6.5 (CI 2.4–17.3) compared with 60+ protocols, and 8.0 (CI 3.1–19.4) with UKALL14. OS was also superior, with a HR of 5.5 (CI 1.8–16.6) with 60+ and 4.7 (CI 1.8–12.6).
The data for T-ALL were also analysed, but not displayed due to small numbers. The median survival when divided by protocol was 9.73 months (CI 2.2–9.7) for COG and not reached for UKALL14.
We then looked at the effect of ethnicity on treatment outcomes. Table 3 summarises the survival outcomes. There was no statistical difference in the OS and EFS with a p-value of 0.42 and 0.55.
Sub-analysis was performed for B-ALL. T-ALL was not analysed due to small numbers. For AYA patients treated on the COG protocol, Māori/Pacific Islanders had a 3-year OS and EFS of 71.4% (SE 0.17) and 72.9% (SE 0.17) respectively, while non-Māori/Pacific Islanders had a 100% OS and EFS. However, this was not statistically significant with a p-value of 0.21 and 0.23 for OS and EFS using the Log-Rank test.
Table 4 details the demographic differences for patients on the UKALL14 protocol, and Figure 4 presents the KM curves for illustrative purposes. There was a statistically significant difference in EFS.
The percentage of patients achieving an MRD-negative remission after induction was 44% for UKALL14, 52% for COG and 31% for 60+ protocols. There was no statistical difference when comparing Māori/Pacific Islanders and non-Māori/Pacific Islanders based on a two-tailed p-value of 1.0 using Fisher’s exact test.
In terms of selected adverse events, seven patients developed asparaginase-associated thrombosis, and three patients developed asparaginase-associated liver failure. Of the patients who had treatment-related mortality, one died from a secondary malignancy, one on the CALGB60+ died from asparaginase-associated liver failure, one on the COG protocol died from methotrexate toxicity and three died from sepsis.
A total of 19/65 (29%) patients received an allo-SCT. Patients who did not have a transplant had a median overall survival of 22 months and a 3-year OS of 36%. Those who received a transplant did not reach median survival but had a 3-year OS of 80%. The Log-Rank test revealed a p-value of 0.0013.
In terms of treatment delay, patients on the UKALL14 and COG protocol had a median delay of 27 days and 10 days respectively. When comparing the ethnicities for all comers, the mean delay was 29 days and 23 days for Māori/Pacific Islanders and non-Māori/Pacific Islanders respectively. The Wilcoxon two-sample test was not statistically significant with a two-sided p-value of 0.97. The most common cause of delays were cytopenias and neutropenic fever.
Discussion
This audit had a number of strengths and limitations. Although it is retrospective, it provides a real-world snapshot of the largest group of adults with ALL treated in New Zealand. However, the numbers remain small, which makes comparison with international groups difficult.
Our outcomes in AYA patients currently appear comparable to international standards. However, in patients who are aged 30 and above treated on the UKALL14 protocol, we may be below international standards. First analysis of the UKALL14 trial for B-ALL found a 3-year EFS of 44% for the control arm at a median follow-up of 50.5 months.[[14,15]] The UKALLXII trial, which recruited adults with T- and B-ALL between 1993 and 2006, had an OS of 38% at 5 years.[[16]] By comparison, our OS with the UKALL14 protocol for both T- and B-ALL at 3 years was 53%, and our EFS for B-ALL patients was 39.7%. There was a statistically significant difference in outcomes between ethnic groups.
We were not able to accurately assess the reasons for this due to the small sample. Despite the fact that most of the deaths were due to relapse, our MRD-negative rates were similar to the international trials.[[9,15]] With respect to the differences between Māori/Pacific Islanders and non-Māori/Pacific Islanders, more non-Māori/Pacific Islander patients were MRD-negative by induction and received an allo-SCT, while Māori and Pacific Islanders had more treatment delays and initial dose alterations due to various toxicities. However, there were no statistically significant differences in treatment delay and achievement of MRD negativity; statistical analysis was not performed for the other parameters. It is important to note that the ability to proceed to a stem cell transplant depends on performance score during chemotherapy and stem cell donor availability. Registry data from South Australia has shown a significant improvement in OS in ALL in the last two decades; this was attributed to the extension of intensive chemotherapy protocols to older patients, improvement in supportive care and possibly increasing numbers of allo-SCTs.[[17]]
Treatment delays during chemotherapy are thought to affect prognosis.[[18,19]] This audit shows that patients treated with the UKALL14 protocol have more delays; this is one aspect where we can potentially improve on.
The available chemotherapeutics are limited in New Zealand, unless trial enrolment is successful. The study drug in the UKALL14 trial, Rituximab, has only just been approved in 2021; we have now incorporated this into our protocol. The lack of ready access to newer novel therapies such as Blinatumomab, Inotuzumab, and CAR-T cells which have proven efficacy in the relapsed setting leading to improved OS remains an ongoing issue. However, Blinatumomab is now available via a Named Patient Pharmaceutical Assessment (NPPA) as a bridge to stem cell transplant for those with MRD levels of >0.1%.[[20]]
Alternative regimens exist. HyperCVAD is used in some New Zealand centres, which can include asparaginase. Outcomes vary internationally, with a 5-year OS between 39–60%.[[21,22]] Paediatric-inspired protocols have been used up to the age of 45; this may be another option to improve our adult outcomes if they can be administered safely.
In conclusion, while the Auckland outcomes of ALL treatment are comparable to international groups, there remains room for improvement, especially in the adult Māori and Pacific Island population. Further research in this area is required.
Summary
Abstract
Aim
Acute lymphoblastic leukaemia/lymphoma (ALL) is a rare disease that requires an intensive chemotherapy regimen for successful treatment. This is a single-centre retrospective audit to assess the treatment outcomes in the largest ALL centre in New Zealand.
Method
Data such as survival and adverse events of patients with de novo ALL referred to Auckland City Hospital for treatment were included in this audit. Sub-group analyses were also performed.
Results
Sixty-five patients aged from 18 upwards with ALL were included in this audit. The median survival of all patients was 37.6 months. Adolescent and young adults (AYA) treated on the COG (paediatric) protocols had a mean survival of 48.3 months (median not reached), while adults treated with the UKALL14 protocol had a median survival of 37.6 months. In the UKALL14 sub-group, Māori/Pacific Islanders had an inferior EFS that was statistically significant.
Conclusion
Overall AYA outcomes are comparable to international standards. Our adult outcomes may be poorer than the original UKALL14 trial, with Māori/Pacific Island patients having shorter survival.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1) Dong Y, Shi O, Zeng Q, Lu X, Wang W, Li Y, Wang Q. Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 2020;9(1):14.
2) Roberts KG. Genetics and prognosis of ALL in children vs adults. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):137-145.
3) Teachey DT, Hunger SP, Loh ML. Optimizing therapy in the modern age: differences in length of maintenance therapy in acute lymphoblastic leukemia. Blood. 2021 Jan 14;137(2):168-77.
4) Arslan S, Pullarkat V, Aldoss I. Indications for Allogeneic HCT in Adults with Acute Lymphoblastic Leukemia in First Complete Remission. Curr Treat Options Oncol. 2021;22(7):63.
5) Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013 Jun;381(9881):1943-55.
6) Siegel SE, Stock W, Johnson RH, Advani A, Muffly L, Douer D, et al. Pediatric-Inspired Treatment Regimens for Adolescents and Young Adults With Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Review. JAMA Oncol. 2018 May 1;4(5):725.
7) Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017 Jun;7(6):e577.
8) Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012 May;87(5):472-8.
9) Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, et al. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-92.
10) Ballantine K, Moss R, Watson H. Adolescent & young adult cancer incidence and survival in otearoa 2008 -2017 [Internet]. AYA Cancer Network Aotearoa; 2020 Aug:46. Available from: https://ayacancernetwork.org.nz/wp-content/uploads/2021/07/AYA-Cancer-Incidence-and-Survival-in-Aotearoa-2008-2017-Released.pdf.
11) Fielding A. UKALL14 - Protocol - v5.0 20.07.12.pdf [Internet]. Cancer Research UK; 2012. Available from: https://redbook.streamliners.co.nz/UKALL14%20-%20Protocol%20-%20v5.0%2020.07.12.pdf.
12) Fielding A. ukall60plus-protocol-v30-21052015.pdf [Internet]. Cancer Research UK; 2015. Available from: https://northerncanceralliance.nhs.uk/wp-content/uploads/2019/01/UKALL60-Protocol-v3.0-21.05.2015.pdf.
13) Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37.
14) Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, et al. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022 Apr;9(4):e262-75.
15) Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, et al. First Analysis of the UKALL14 Phase 3 Randomised Trial to Determine If the Addition of Rituximab to Standard Induction Chemotherapy Improves EFS in Adults with Precursor B-ALL (CRUK/09/006). Blood. 2019 Nov 13;134(Supplement_1):739-739.
16) Rowe JM Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760–7.
17) Beckmann K, Kearney BJ AM, Yeung D, Hiwase D, Li M, Roder DM. Changes in five‐year survival for people with acute leukaemia in South Australia, 1980-2016. Med J Aust. 2022;216(6);296-302.
18) Kumar AJ, Gimotty PA, Gelfand JM, Buck G, Rowe JM, Goldstone AH, et al. Delays in postremission chemotherapy for Philadelphia chromosome negative acute lymphoblastic leukemia are associated with inferior outcomes in patients who undergo allogeneic transplant: An analysis from ECOG 2993/MRC UK ALLXII. Am J Hematol. 2016 Nov;91(11):1107-12.
19) Agrawal V, Kayal S, Ganesan P, Dubashi B. Chemotherapy Delays Are Associated with Inferior Outcome in Acute Lymphoblastic Leukemia: A Retrospective Study from a Tertiary Cancer Center in South India. Indian J Med Paediatr Oncol. 2021 Mar;42(1):51-60.
20) DuVall AS, Sheade J, Anderson D, Yates SJ, Stock W. Updates in the Management of Relapsed and Refractory Acute Lymphoblastic Leukemia: An Urgent Plea for New Treatments Is Being Answered! JCO Oncol Pract. 2022 Jul;18(7):479-87.
21) Kantarjian H, Thomas D, O’Brien S, Cortes J, et al. Long‐term follow‐up results of hyperfractionated cyclophosphamide vincristine doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec;101(12):2788-2801.
22) Siegel SE, Advani A, Seibel N, Muffly L, Stock W, Luger S, et al. Treatment of young adults with Philadelphia-negative acute lymphoblastic leukemia and lymphoblastic lymphoma: Hyper-CVAD vs. pediatric-inspired regimens. Am J Hematol. 2018 Oct;93(10):1254-66.
For the PDF of this article,
contact nzmj@nzma.org.nz
Treatment outcomes of adult acute lymphoblastic leukaemia in Auckland, New Zealand
View Article PDF
Introduction
Acute lymphoblastic leukaemia (ALL) is a neoplasm of immature lymphoid cells. The estimated incidence world-wide in 2017 was 0.85 per 100,000.[[1]] It is classically divided into T- and B-cell lineages. Presenting features include cytopenias, lymphadenopathy and organ infiltration.
The treatment of ALL involves multi-agent chemotherapy. An initial intensive phase lasts 6 to 9 months, with a subsequent maintenance phase lasting for up to 2 years. The goal is to achieve a measurable residual disease (MRD) negative status, where leukaemic cells are unable to be detected using current techniques; this is associated with superior outcomes.[[2,3]] Allogeneic stem cell transplantation (allo-SCT) is recommended in those who do not attain an MRD-negative state or who have high-risk genetics.[[4]]
Outcomes in children are excellent, with a 5-year overall survival (OS) exceeding 90%.[[5]] However, the OS in adults historically ranges from 5 to 55%.[[2,6,7]] This may be due to a) treatment with less intensive regimens due to risk of adverse events, b) comorbidities, c) higher incidence of high-risk genetics, d) treatment delays due to toxicity, and e) comparative lack of ancillary services and support in older patients. Adolescents and young adults (AYA), which is defined as age from 10 up to 39, is a unique sub-group. These patients (and potentially patients up to 45 years old) when treated with paediatric protocols do better compared with adult protocols, with one review finding a relative risk of 0.55 for all-cause mortality at 3 years favouring paediatric regimens.[[8]] In the very high-risk category of patients (which includes all patients aged between 13 and 30) treated on the COG1131 trial, the 4-year disease-free survival was 76%.[[9]] New Zealand data from between 2008 and 2017 found that the 5-year survival in the 15–24-year-old cohort improved from 68% to 79% overall. However, survival in Māori/Pacific Islanders remain lower than non-Māori/Pacific Islanders, with the 5-year survival being 75%, 73% and 82% respectively.[[10]]
In the Northern region all patients aged 16 and over who are candidates for curative therapy are referred to the adult haematology department at Auckland City Hospital (ACH). From 2018, all AYA ALL patients in the former Waikato District Health Board (DHB) were referred, and from early 2019 all AYA patients in MidCentral DHB were also referred in to ACH. AYA patients aged between 16 and 30 are treated using Children’s Oncology Group (COG) protocols within a trial or on the control arm of the most recent trial. Adults aged from 31 up to 60 are treated using the control arm of the UKALL14 protocol; the UKALL14 is the latest adult ALL trial from the UK.[[11]] Adults aged above 60 are treated using CALGB8811 (called CALGB60+) or UKALL60+ protocols based on fitness; these regimens are less intensive compared to the UKALL14.[[12,13]] The CALGB60+ is of an intermediate intensity between the UKALL protocols, while the UKALL60+ is of lower intensity and does not contain asparaginase. The protocols are adapted based on funded drugs. Allo-SCTs were carried out according to protocols if a donor could be identified.
The aim of this audit was therefore to review the characteristics and outcomes of ALL patients treated by the adult haematology service at ACH between 2016 and 2021.
Methods
Study design and data sources
This was an audit conducted by the adult haematology department at ACH. Data including patient details and selected clinical outcomes was collected prospectively for all de novo patients referred to ACH with confirmed ALL, biphenotypic acute leukaemia that included a lymphoid lineage, or CML in lymphoid blast crisis from June 2016. If the diagnostic bone marrow biopsy found <25% morphologic blasts, this was considered a B- or T-lymphoblastic lymphoma (LLy). We then retrospectively collected additional data from electronic hospital records, including demographics and other specific outcomes such as adverse events and treatment delay, into the database. This was anonymised, password protected and then analysed. Community records were not accessed as essentially all relevant care was conducted by the department. Institutional and ethical approval was sought from the Auckland City Hospital Research Office but was deemed to be not required.
Inclusion criteria
Patients in the database from 1 June 2016 to 1 November 2021 were included in this analysis. Patients who commenced therapy overseas but were transferred to ACH after induction were also included.
Exclusion criteria
Patients who were referred to ACH purely for allo-SCT and those predominantly treated overseas were excluded.
Definitions
The diagnosis of ALL was based on the consensus opinion of the Auckland acute leukaemia multi-disciplinary meeting. The date of diagnosis was based on the date of the first bone marrow biopsy.
Event-free survival (EFS) was defined as the time from diagnosis until a relapse or primary refractory state was diagnosed on a bone marrow or peripheral blood specimen, or death.
Complete remission was defined as <5% leukaemic blasts on a bone marrow biopsy. MRD was determined by flow cytometry (for B-ALL, COG standard (3 tube, 6 colour panel) and leukaemia-specific phenotype for T-ALL) for the purposes of this audit; a negative state was defined as <0.01%.
If a patient died after a diagnosis of relapsed or refractory disease, then this was considered the cause of death. Otherwise, deaths were defined as treatment related—for example, sepsis or liver failure. If the patient died of an unrelated cause, this was considered treatment unrelated.
The COG category included all patients treated with on a COG protocol, 1131 and 1732 for B-ALL and 1231 for T-ALL. The 60+ category included those treated with CALGB60+ and UKALL60+. The UKALL14 category is standalone. A few patients were treated with other protocols, and were included in the survival analysis but not displayed on selected KM curves due to the small numbers.
For the analysis of treatment delays, the minimum days in each phase of treatment was subtracted from the actual days.
Statistical analysis
A statistician (RH) was employed to perform statistical analysis using the SAS 9.4 programme. The Log-Rank test was used to determine statistical significance via Kaplan–Meier (KM) curves for differences in outcome. Other analytical methods are presented with the relevant results below. All confidence intervals (CI) displayed are of 95% percentile.
Results
A total of 65 patients were included in this audit. There were 52 B-ALL and 13 T-ALL patients. Table 1 summarises the demographic data.
View Table 1–4 and Figures 1–4.
Overall, 27 patients (41%) died during the study period. Of these, five (19%) were due to primary refractory disease, 14 (52%) were due to relapse, and seven (26%) due to treatment related mortality. One patient relapsed but died of a treatment unrelated ruptured aortic aneurysm.
The median OS was 37.6 months, 37 months, and not reached (NR) for all patients, B-ALL and T-ALL respectively. The median PFS was 30.2 months for B-ALL, and NR for T-ALL. The 3-year OS and EFS was 51% (standard error [SE)] 0.07) and 50% (SE 0.07) for all comers, 47% (SE 0.09) and 45% (SE 0.09) for B-ALL, and 62% (SE 0.13) and 62% (SE 0.13) for T-ALL respectively. Figure 1 displays the KM curves for OS and EFS.
When classified by protocol, the median OS and 3-year OS was 27.5 months (confidence interval [CI] 9.8–42.0) and 19% (SE 0.16) for 60+; 37.6 months (CI 11.7–37.6) and 53% (SE 0.11) for UKALL14. The median OS was not reached for COG, but the 3-year OS was 72% (SE 0.11). Figure 2 displays the KM curve.
Figure 3 displays the outcomes for B-ALL only, and demonstrates the effect of age and treatment protocol on outcomes. Table 2 shows the 3-year survival outcomes. Despite the small numbers, patients treated with COG have a statistically superior EFS with a HR of 6.5 (CI 2.4–17.3) compared with 60+ protocols, and 8.0 (CI 3.1–19.4) with UKALL14. OS was also superior, with a HR of 5.5 (CI 1.8–16.6) with 60+ and 4.7 (CI 1.8–12.6).
The data for T-ALL were also analysed, but not displayed due to small numbers. The median survival when divided by protocol was 9.73 months (CI 2.2–9.7) for COG and not reached for UKALL14.
We then looked at the effect of ethnicity on treatment outcomes. Table 3 summarises the survival outcomes. There was no statistical difference in the OS and EFS with a p-value of 0.42 and 0.55.
Sub-analysis was performed for B-ALL. T-ALL was not analysed due to small numbers. For AYA patients treated on the COG protocol, Māori/Pacific Islanders had a 3-year OS and EFS of 71.4% (SE 0.17) and 72.9% (SE 0.17) respectively, while non-Māori/Pacific Islanders had a 100% OS and EFS. However, this was not statistically significant with a p-value of 0.21 and 0.23 for OS and EFS using the Log-Rank test.
Table 4 details the demographic differences for patients on the UKALL14 protocol, and Figure 4 presents the KM curves for illustrative purposes. There was a statistically significant difference in EFS.
The percentage of patients achieving an MRD-negative remission after induction was 44% for UKALL14, 52% for COG and 31% for 60+ protocols. There was no statistical difference when comparing Māori/Pacific Islanders and non-Māori/Pacific Islanders based on a two-tailed p-value of 1.0 using Fisher’s exact test.
In terms of selected adverse events, seven patients developed asparaginase-associated thrombosis, and three patients developed asparaginase-associated liver failure. Of the patients who had treatment-related mortality, one died from a secondary malignancy, one on the CALGB60+ died from asparaginase-associated liver failure, one on the COG protocol died from methotrexate toxicity and three died from sepsis.
A total of 19/65 (29%) patients received an allo-SCT. Patients who did not have a transplant had a median overall survival of 22 months and a 3-year OS of 36%. Those who received a transplant did not reach median survival but had a 3-year OS of 80%. The Log-Rank test revealed a p-value of 0.0013.
In terms of treatment delay, patients on the UKALL14 and COG protocol had a median delay of 27 days and 10 days respectively. When comparing the ethnicities for all comers, the mean delay was 29 days and 23 days for Māori/Pacific Islanders and non-Māori/Pacific Islanders respectively. The Wilcoxon two-sample test was not statistically significant with a two-sided p-value of 0.97. The most common cause of delays were cytopenias and neutropenic fever.
Discussion
This audit had a number of strengths and limitations. Although it is retrospective, it provides a real-world snapshot of the largest group of adults with ALL treated in New Zealand. However, the numbers remain small, which makes comparison with international groups difficult.
Our outcomes in AYA patients currently appear comparable to international standards. However, in patients who are aged 30 and above treated on the UKALL14 protocol, we may be below international standards. First analysis of the UKALL14 trial for B-ALL found a 3-year EFS of 44% for the control arm at a median follow-up of 50.5 months.[[14,15]] The UKALLXII trial, which recruited adults with T- and B-ALL between 1993 and 2006, had an OS of 38% at 5 years.[[16]] By comparison, our OS with the UKALL14 protocol for both T- and B-ALL at 3 years was 53%, and our EFS for B-ALL patients was 39.7%. There was a statistically significant difference in outcomes between ethnic groups.
We were not able to accurately assess the reasons for this due to the small sample. Despite the fact that most of the deaths were due to relapse, our MRD-negative rates were similar to the international trials.[[9,15]] With respect to the differences between Māori/Pacific Islanders and non-Māori/Pacific Islanders, more non-Māori/Pacific Islander patients were MRD-negative by induction and received an allo-SCT, while Māori and Pacific Islanders had more treatment delays and initial dose alterations due to various toxicities. However, there were no statistically significant differences in treatment delay and achievement of MRD negativity; statistical analysis was not performed for the other parameters. It is important to note that the ability to proceed to a stem cell transplant depends on performance score during chemotherapy and stem cell donor availability. Registry data from South Australia has shown a significant improvement in OS in ALL in the last two decades; this was attributed to the extension of intensive chemotherapy protocols to older patients, improvement in supportive care and possibly increasing numbers of allo-SCTs.[[17]]
Treatment delays during chemotherapy are thought to affect prognosis.[[18,19]] This audit shows that patients treated with the UKALL14 protocol have more delays; this is one aspect where we can potentially improve on.
The available chemotherapeutics are limited in New Zealand, unless trial enrolment is successful. The study drug in the UKALL14 trial, Rituximab, has only just been approved in 2021; we have now incorporated this into our protocol. The lack of ready access to newer novel therapies such as Blinatumomab, Inotuzumab, and CAR-T cells which have proven efficacy in the relapsed setting leading to improved OS remains an ongoing issue. However, Blinatumomab is now available via a Named Patient Pharmaceutical Assessment (NPPA) as a bridge to stem cell transplant for those with MRD levels of >0.1%.[[20]]
Alternative regimens exist. HyperCVAD is used in some New Zealand centres, which can include asparaginase. Outcomes vary internationally, with a 5-year OS between 39–60%.[[21,22]] Paediatric-inspired protocols have been used up to the age of 45; this may be another option to improve our adult outcomes if they can be administered safely.
In conclusion, while the Auckland outcomes of ALL treatment are comparable to international groups, there remains room for improvement, especially in the adult Māori and Pacific Island population. Further research in this area is required.
Summary
Abstract
Aim
Acute lymphoblastic leukaemia/lymphoma (ALL) is a rare disease that requires an intensive chemotherapy regimen for successful treatment. This is a single-centre retrospective audit to assess the treatment outcomes in the largest ALL centre in New Zealand.
Method
Data such as survival and adverse events of patients with de novo ALL referred to Auckland City Hospital for treatment were included in this audit. Sub-group analyses were also performed.
Results
Sixty-five patients aged from 18 upwards with ALL were included in this audit. The median survival of all patients was 37.6 months. Adolescent and young adults (AYA) treated on the COG (paediatric) protocols had a mean survival of 48.3 months (median not reached), while adults treated with the UKALL14 protocol had a median survival of 37.6 months. In the UKALL14 sub-group, Māori/Pacific Islanders had an inferior EFS that was statistically significant.
Conclusion
Overall AYA outcomes are comparable to international standards. Our adult outcomes may be poorer than the original UKALL14 trial, with Māori/Pacific Island patients having shorter survival.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1) Dong Y, Shi O, Zeng Q, Lu X, Wang W, Li Y, Wang Q. Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 2020;9(1):14.
2) Roberts KG. Genetics and prognosis of ALL in children vs adults. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):137-145.
3) Teachey DT, Hunger SP, Loh ML. Optimizing therapy in the modern age: differences in length of maintenance therapy in acute lymphoblastic leukemia. Blood. 2021 Jan 14;137(2):168-77.
4) Arslan S, Pullarkat V, Aldoss I. Indications for Allogeneic HCT in Adults with Acute Lymphoblastic Leukemia in First Complete Remission. Curr Treat Options Oncol. 2021;22(7):63.
5) Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013 Jun;381(9881):1943-55.
6) Siegel SE, Stock W, Johnson RH, Advani A, Muffly L, Douer D, et al. Pediatric-Inspired Treatment Regimens for Adolescents and Young Adults With Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Review. JAMA Oncol. 2018 May 1;4(5):725.
7) Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017 Jun;7(6):e577.
8) Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012 May;87(5):472-8.
9) Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, et al. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-92.
10) Ballantine K, Moss R, Watson H. Adolescent & young adult cancer incidence and survival in otearoa 2008 -2017 [Internet]. AYA Cancer Network Aotearoa; 2020 Aug:46. Available from: https://ayacancernetwork.org.nz/wp-content/uploads/2021/07/AYA-Cancer-Incidence-and-Survival-in-Aotearoa-2008-2017-Released.pdf.
11) Fielding A. UKALL14 - Protocol - v5.0 20.07.12.pdf [Internet]. Cancer Research UK; 2012. Available from: https://redbook.streamliners.co.nz/UKALL14%20-%20Protocol%20-%20v5.0%2020.07.12.pdf.
12) Fielding A. ukall60plus-protocol-v30-21052015.pdf [Internet]. Cancer Research UK; 2015. Available from: https://northerncanceralliance.nhs.uk/wp-content/uploads/2019/01/UKALL60-Protocol-v3.0-21.05.2015.pdf.
13) Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37.
14) Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, et al. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022 Apr;9(4):e262-75.
15) Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, et al. First Analysis of the UKALL14 Phase 3 Randomised Trial to Determine If the Addition of Rituximab to Standard Induction Chemotherapy Improves EFS in Adults with Precursor B-ALL (CRUK/09/006). Blood. 2019 Nov 13;134(Supplement_1):739-739.
16) Rowe JM Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760–7.
17) Beckmann K, Kearney BJ AM, Yeung D, Hiwase D, Li M, Roder DM. Changes in five‐year survival for people with acute leukaemia in South Australia, 1980-2016. Med J Aust. 2022;216(6);296-302.
18) Kumar AJ, Gimotty PA, Gelfand JM, Buck G, Rowe JM, Goldstone AH, et al. Delays in postremission chemotherapy for Philadelphia chromosome negative acute lymphoblastic leukemia are associated with inferior outcomes in patients who undergo allogeneic transplant: An analysis from ECOG 2993/MRC UK ALLXII. Am J Hematol. 2016 Nov;91(11):1107-12.
19) Agrawal V, Kayal S, Ganesan P, Dubashi B. Chemotherapy Delays Are Associated with Inferior Outcome in Acute Lymphoblastic Leukemia: A Retrospective Study from a Tertiary Cancer Center in South India. Indian J Med Paediatr Oncol. 2021 Mar;42(1):51-60.
20) DuVall AS, Sheade J, Anderson D, Yates SJ, Stock W. Updates in the Management of Relapsed and Refractory Acute Lymphoblastic Leukemia: An Urgent Plea for New Treatments Is Being Answered! JCO Oncol Pract. 2022 Jul;18(7):479-87.
21) Kantarjian H, Thomas D, O’Brien S, Cortes J, et al. Long‐term follow‐up results of hyperfractionated cyclophosphamide vincristine doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec;101(12):2788-2801.
22) Siegel SE, Advani A, Seibel N, Muffly L, Stock W, Luger S, et al. Treatment of young adults with Philadelphia-negative acute lymphoblastic leukemia and lymphoblastic lymphoma: Hyper-CVAD vs. pediatric-inspired regimens. Am J Hematol. 2018 Oct;93(10):1254-66.
For the PDF of this article,
contact nzmj@nzma.org.nz
Treatment outcomes of adult acute lymphoblastic leukaemia in Auckland, New Zealand
View Article PDF
Introduction
Acute lymphoblastic leukaemia (ALL) is a neoplasm of immature lymphoid cells. The estimated incidence world-wide in 2017 was 0.85 per 100,000.[[1]] It is classically divided into T- and B-cell lineages. Presenting features include cytopenias, lymphadenopathy and organ infiltration.
The treatment of ALL involves multi-agent chemotherapy. An initial intensive phase lasts 6 to 9 months, with a subsequent maintenance phase lasting for up to 2 years. The goal is to achieve a measurable residual disease (MRD) negative status, where leukaemic cells are unable to be detected using current techniques; this is associated with superior outcomes.[[2,3]] Allogeneic stem cell transplantation (allo-SCT) is recommended in those who do not attain an MRD-negative state or who have high-risk genetics.[[4]]
Outcomes in children are excellent, with a 5-year overall survival (OS) exceeding 90%.[[5]] However, the OS in adults historically ranges from 5 to 55%.[[2,6,7]] This may be due to a) treatment with less intensive regimens due to risk of adverse events, b) comorbidities, c) higher incidence of high-risk genetics, d) treatment delays due to toxicity, and e) comparative lack of ancillary services and support in older patients. Adolescents and young adults (AYA), which is defined as age from 10 up to 39, is a unique sub-group. These patients (and potentially patients up to 45 years old) when treated with paediatric protocols do better compared with adult protocols, with one review finding a relative risk of 0.55 for all-cause mortality at 3 years favouring paediatric regimens.[[8]] In the very high-risk category of patients (which includes all patients aged between 13 and 30) treated on the COG1131 trial, the 4-year disease-free survival was 76%.[[9]] New Zealand data from between 2008 and 2017 found that the 5-year survival in the 15–24-year-old cohort improved from 68% to 79% overall. However, survival in Māori/Pacific Islanders remain lower than non-Māori/Pacific Islanders, with the 5-year survival being 75%, 73% and 82% respectively.[[10]]
In the Northern region all patients aged 16 and over who are candidates for curative therapy are referred to the adult haematology department at Auckland City Hospital (ACH). From 2018, all AYA ALL patients in the former Waikato District Health Board (DHB) were referred, and from early 2019 all AYA patients in MidCentral DHB were also referred in to ACH. AYA patients aged between 16 and 30 are treated using Children’s Oncology Group (COG) protocols within a trial or on the control arm of the most recent trial. Adults aged from 31 up to 60 are treated using the control arm of the UKALL14 protocol; the UKALL14 is the latest adult ALL trial from the UK.[[11]] Adults aged above 60 are treated using CALGB8811 (called CALGB60+) or UKALL60+ protocols based on fitness; these regimens are less intensive compared to the UKALL14.[[12,13]] The CALGB60+ is of an intermediate intensity between the UKALL protocols, while the UKALL60+ is of lower intensity and does not contain asparaginase. The protocols are adapted based on funded drugs. Allo-SCTs were carried out according to protocols if a donor could be identified.
The aim of this audit was therefore to review the characteristics and outcomes of ALL patients treated by the adult haematology service at ACH between 2016 and 2021.
Methods
Study design and data sources
This was an audit conducted by the adult haematology department at ACH. Data including patient details and selected clinical outcomes was collected prospectively for all de novo patients referred to ACH with confirmed ALL, biphenotypic acute leukaemia that included a lymphoid lineage, or CML in lymphoid blast crisis from June 2016. If the diagnostic bone marrow biopsy found <25% morphologic blasts, this was considered a B- or T-lymphoblastic lymphoma (LLy). We then retrospectively collected additional data from electronic hospital records, including demographics and other specific outcomes such as adverse events and treatment delay, into the database. This was anonymised, password protected and then analysed. Community records were not accessed as essentially all relevant care was conducted by the department. Institutional and ethical approval was sought from the Auckland City Hospital Research Office but was deemed to be not required.
Inclusion criteria
Patients in the database from 1 June 2016 to 1 November 2021 were included in this analysis. Patients who commenced therapy overseas but were transferred to ACH after induction were also included.
Exclusion criteria
Patients who were referred to ACH purely for allo-SCT and those predominantly treated overseas were excluded.
Definitions
The diagnosis of ALL was based on the consensus opinion of the Auckland acute leukaemia multi-disciplinary meeting. The date of diagnosis was based on the date of the first bone marrow biopsy.
Event-free survival (EFS) was defined as the time from diagnosis until a relapse or primary refractory state was diagnosed on a bone marrow or peripheral blood specimen, or death.
Complete remission was defined as <5% leukaemic blasts on a bone marrow biopsy. MRD was determined by flow cytometry (for B-ALL, COG standard (3 tube, 6 colour panel) and leukaemia-specific phenotype for T-ALL) for the purposes of this audit; a negative state was defined as <0.01%.
If a patient died after a diagnosis of relapsed or refractory disease, then this was considered the cause of death. Otherwise, deaths were defined as treatment related—for example, sepsis or liver failure. If the patient died of an unrelated cause, this was considered treatment unrelated.
The COG category included all patients treated with on a COG protocol, 1131 and 1732 for B-ALL and 1231 for T-ALL. The 60+ category included those treated with CALGB60+ and UKALL60+. The UKALL14 category is standalone. A few patients were treated with other protocols, and were included in the survival analysis but not displayed on selected KM curves due to the small numbers.
For the analysis of treatment delays, the minimum days in each phase of treatment was subtracted from the actual days.
Statistical analysis
A statistician (RH) was employed to perform statistical analysis using the SAS 9.4 programme. The Log-Rank test was used to determine statistical significance via Kaplan–Meier (KM) curves for differences in outcome. Other analytical methods are presented with the relevant results below. All confidence intervals (CI) displayed are of 95% percentile.
Results
A total of 65 patients were included in this audit. There were 52 B-ALL and 13 T-ALL patients. Table 1 summarises the demographic data.
View Table 1–4 and Figures 1–4.
Overall, 27 patients (41%) died during the study period. Of these, five (19%) were due to primary refractory disease, 14 (52%) were due to relapse, and seven (26%) due to treatment related mortality. One patient relapsed but died of a treatment unrelated ruptured aortic aneurysm.
The median OS was 37.6 months, 37 months, and not reached (NR) for all patients, B-ALL and T-ALL respectively. The median PFS was 30.2 months for B-ALL, and NR for T-ALL. The 3-year OS and EFS was 51% (standard error [SE)] 0.07) and 50% (SE 0.07) for all comers, 47% (SE 0.09) and 45% (SE 0.09) for B-ALL, and 62% (SE 0.13) and 62% (SE 0.13) for T-ALL respectively. Figure 1 displays the KM curves for OS and EFS.
When classified by protocol, the median OS and 3-year OS was 27.5 months (confidence interval [CI] 9.8–42.0) and 19% (SE 0.16) for 60+; 37.6 months (CI 11.7–37.6) and 53% (SE 0.11) for UKALL14. The median OS was not reached for COG, but the 3-year OS was 72% (SE 0.11). Figure 2 displays the KM curve.
Figure 3 displays the outcomes for B-ALL only, and demonstrates the effect of age and treatment protocol on outcomes. Table 2 shows the 3-year survival outcomes. Despite the small numbers, patients treated with COG have a statistically superior EFS with a HR of 6.5 (CI 2.4–17.3) compared with 60+ protocols, and 8.0 (CI 3.1–19.4) with UKALL14. OS was also superior, with a HR of 5.5 (CI 1.8–16.6) with 60+ and 4.7 (CI 1.8–12.6).
The data for T-ALL were also analysed, but not displayed due to small numbers. The median survival when divided by protocol was 9.73 months (CI 2.2–9.7) for COG and not reached for UKALL14.
We then looked at the effect of ethnicity on treatment outcomes. Table 3 summarises the survival outcomes. There was no statistical difference in the OS and EFS with a p-value of 0.42 and 0.55.
Sub-analysis was performed for B-ALL. T-ALL was not analysed due to small numbers. For AYA patients treated on the COG protocol, Māori/Pacific Islanders had a 3-year OS and EFS of 71.4% (SE 0.17) and 72.9% (SE 0.17) respectively, while non-Māori/Pacific Islanders had a 100% OS and EFS. However, this was not statistically significant with a p-value of 0.21 and 0.23 for OS and EFS using the Log-Rank test.
Table 4 details the demographic differences for patients on the UKALL14 protocol, and Figure 4 presents the KM curves for illustrative purposes. There was a statistically significant difference in EFS.
The percentage of patients achieving an MRD-negative remission after induction was 44% for UKALL14, 52% for COG and 31% for 60+ protocols. There was no statistical difference when comparing Māori/Pacific Islanders and non-Māori/Pacific Islanders based on a two-tailed p-value of 1.0 using Fisher’s exact test.
In terms of selected adverse events, seven patients developed asparaginase-associated thrombosis, and three patients developed asparaginase-associated liver failure. Of the patients who had treatment-related mortality, one died from a secondary malignancy, one on the CALGB60+ died from asparaginase-associated liver failure, one on the COG protocol died from methotrexate toxicity and three died from sepsis.
A total of 19/65 (29%) patients received an allo-SCT. Patients who did not have a transplant had a median overall survival of 22 months and a 3-year OS of 36%. Those who received a transplant did not reach median survival but had a 3-year OS of 80%. The Log-Rank test revealed a p-value of 0.0013.
In terms of treatment delay, patients on the UKALL14 and COG protocol had a median delay of 27 days and 10 days respectively. When comparing the ethnicities for all comers, the mean delay was 29 days and 23 days for Māori/Pacific Islanders and non-Māori/Pacific Islanders respectively. The Wilcoxon two-sample test was not statistically significant with a two-sided p-value of 0.97. The most common cause of delays were cytopenias and neutropenic fever.
Discussion
This audit had a number of strengths and limitations. Although it is retrospective, it provides a real-world snapshot of the largest group of adults with ALL treated in New Zealand. However, the numbers remain small, which makes comparison with international groups difficult.
Our outcomes in AYA patients currently appear comparable to international standards. However, in patients who are aged 30 and above treated on the UKALL14 protocol, we may be below international standards. First analysis of the UKALL14 trial for B-ALL found a 3-year EFS of 44% for the control arm at a median follow-up of 50.5 months.[[14,15]] The UKALLXII trial, which recruited adults with T- and B-ALL between 1993 and 2006, had an OS of 38% at 5 years.[[16]] By comparison, our OS with the UKALL14 protocol for both T- and B-ALL at 3 years was 53%, and our EFS for B-ALL patients was 39.7%. There was a statistically significant difference in outcomes between ethnic groups.
We were not able to accurately assess the reasons for this due to the small sample. Despite the fact that most of the deaths were due to relapse, our MRD-negative rates were similar to the international trials.[[9,15]] With respect to the differences between Māori/Pacific Islanders and non-Māori/Pacific Islanders, more non-Māori/Pacific Islander patients were MRD-negative by induction and received an allo-SCT, while Māori and Pacific Islanders had more treatment delays and initial dose alterations due to various toxicities. However, there were no statistically significant differences in treatment delay and achievement of MRD negativity; statistical analysis was not performed for the other parameters. It is important to note that the ability to proceed to a stem cell transplant depends on performance score during chemotherapy and stem cell donor availability. Registry data from South Australia has shown a significant improvement in OS in ALL in the last two decades; this was attributed to the extension of intensive chemotherapy protocols to older patients, improvement in supportive care and possibly increasing numbers of allo-SCTs.[[17]]
Treatment delays during chemotherapy are thought to affect prognosis.[[18,19]] This audit shows that patients treated with the UKALL14 protocol have more delays; this is one aspect where we can potentially improve on.
The available chemotherapeutics are limited in New Zealand, unless trial enrolment is successful. The study drug in the UKALL14 trial, Rituximab, has only just been approved in 2021; we have now incorporated this into our protocol. The lack of ready access to newer novel therapies such as Blinatumomab, Inotuzumab, and CAR-T cells which have proven efficacy in the relapsed setting leading to improved OS remains an ongoing issue. However, Blinatumomab is now available via a Named Patient Pharmaceutical Assessment (NPPA) as a bridge to stem cell transplant for those with MRD levels of >0.1%.[[20]]
Alternative regimens exist. HyperCVAD is used in some New Zealand centres, which can include asparaginase. Outcomes vary internationally, with a 5-year OS between 39–60%.[[21,22]] Paediatric-inspired protocols have been used up to the age of 45; this may be another option to improve our adult outcomes if they can be administered safely.
In conclusion, while the Auckland outcomes of ALL treatment are comparable to international groups, there remains room for improvement, especially in the adult Māori and Pacific Island population. Further research in this area is required.
Summary
Abstract
Aim
Acute lymphoblastic leukaemia/lymphoma (ALL) is a rare disease that requires an intensive chemotherapy regimen for successful treatment. This is a single-centre retrospective audit to assess the treatment outcomes in the largest ALL centre in New Zealand.
Method
Data such as survival and adverse events of patients with de novo ALL referred to Auckland City Hospital for treatment were included in this audit. Sub-group analyses were also performed.
Results
Sixty-five patients aged from 18 upwards with ALL were included in this audit. The median survival of all patients was 37.6 months. Adolescent and young adults (AYA) treated on the COG (paediatric) protocols had a mean survival of 48.3 months (median not reached), while adults treated with the UKALL14 protocol had a median survival of 37.6 months. In the UKALL14 sub-group, Māori/Pacific Islanders had an inferior EFS that was statistically significant.
Conclusion
Overall AYA outcomes are comparable to international standards. Our adult outcomes may be poorer than the original UKALL14 trial, with Māori/Pacific Island patients having shorter survival.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1) Dong Y, Shi O, Zeng Q, Lu X, Wang W, Li Y, Wang Q. Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 2020;9(1):14.
2) Roberts KG. Genetics and prognosis of ALL in children vs adults. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):137-145.
3) Teachey DT, Hunger SP, Loh ML. Optimizing therapy in the modern age: differences in length of maintenance therapy in acute lymphoblastic leukemia. Blood. 2021 Jan 14;137(2):168-77.
4) Arslan S, Pullarkat V, Aldoss I. Indications for Allogeneic HCT in Adults with Acute Lymphoblastic Leukemia in First Complete Remission. Curr Treat Options Oncol. 2021;22(7):63.
5) Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013 Jun;381(9881):1943-55.
6) Siegel SE, Stock W, Johnson RH, Advani A, Muffly L, Douer D, et al. Pediatric-Inspired Treatment Regimens for Adolescents and Young Adults With Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Review. JAMA Oncol. 2018 May 1;4(5):725.
7) Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017 Jun;7(6):e577.
8) Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012 May;87(5):472-8.
9) Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, et al. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-92.
10) Ballantine K, Moss R, Watson H. Adolescent & young adult cancer incidence and survival in otearoa 2008 -2017 [Internet]. AYA Cancer Network Aotearoa; 2020 Aug:46. Available from: https://ayacancernetwork.org.nz/wp-content/uploads/2021/07/AYA-Cancer-Incidence-and-Survival-in-Aotearoa-2008-2017-Released.pdf.
11) Fielding A. UKALL14 - Protocol - v5.0 20.07.12.pdf [Internet]. Cancer Research UK; 2012. Available from: https://redbook.streamliners.co.nz/UKALL14%20-%20Protocol%20-%20v5.0%2020.07.12.pdf.
12) Fielding A. ukall60plus-protocol-v30-21052015.pdf [Internet]. Cancer Research UK; 2015. Available from: https://northerncanceralliance.nhs.uk/wp-content/uploads/2019/01/UKALL60-Protocol-v3.0-21.05.2015.pdf.
13) Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37.
14) Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, et al. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022 Apr;9(4):e262-75.
15) Marks DI, Kirkwood AA, Rowntree CJ, Aguiar M, Bailey KE, Beaton B, et al. First Analysis of the UKALL14 Phase 3 Randomised Trial to Determine If the Addition of Rituximab to Standard Induction Chemotherapy Improves EFS in Adults with Precursor B-ALL (CRUK/09/006). Blood. 2019 Nov 13;134(Supplement_1):739-739.
16) Rowe JM Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760–7.
17) Beckmann K, Kearney BJ AM, Yeung D, Hiwase D, Li M, Roder DM. Changes in five‐year survival for people with acute leukaemia in South Australia, 1980-2016. Med J Aust. 2022;216(6);296-302.
18) Kumar AJ, Gimotty PA, Gelfand JM, Buck G, Rowe JM, Goldstone AH, et al. Delays in postremission chemotherapy for Philadelphia chromosome negative acute lymphoblastic leukemia are associated with inferior outcomes in patients who undergo allogeneic transplant: An analysis from ECOG 2993/MRC UK ALLXII. Am J Hematol. 2016 Nov;91(11):1107-12.
19) Agrawal V, Kayal S, Ganesan P, Dubashi B. Chemotherapy Delays Are Associated with Inferior Outcome in Acute Lymphoblastic Leukemia: A Retrospective Study from a Tertiary Cancer Center in South India. Indian J Med Paediatr Oncol. 2021 Mar;42(1):51-60.
20) DuVall AS, Sheade J, Anderson D, Yates SJ, Stock W. Updates in the Management of Relapsed and Refractory Acute Lymphoblastic Leukemia: An Urgent Plea for New Treatments Is Being Answered! JCO Oncol Pract. 2022 Jul;18(7):479-87.
21) Kantarjian H, Thomas D, O’Brien S, Cortes J, et al. Long‐term follow‐up results of hyperfractionated cyclophosphamide vincristine doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec;101(12):2788-2801.
22) Siegel SE, Advani A, Seibel N, Muffly L, Stock W, Luger S, et al. Treatment of young adults with Philadelphia-negative acute lymphoblastic leukemia and lymphoblastic lymphoma: Hyper-CVAD vs. pediatric-inspired regimens. Am J Hematol. 2018 Oct;93(10):1254-66.
Contact diana@nzma.org.nz
for the PDF of this article
Treatment outcomes of adult acute lymphoblastic leukaemia in Auckland, New Zealand
Acute lymphoblastic leukaemia (ALL) is a neoplasm of immature lymphoid cells.
Subscriber Content
The full contents of this pages only available to subscribers.
Login, subscribe or email nzmj@nzma.org.nz to purchase this article.
