A Retrospective Analysis of Autologous Stem Cell Transplantation Outcomes in Adult Philadelphia Chromosome Positive-Acute Lymphoblastic Leukemia
CC BY 4.0 · Indian J Med Paediatr Oncol 2023; 44(04): 408-413
DOI: DOI: 10.1055/s-0043-1761413
Abstract
Introduction Philadelphia chromosome positivity (Ph + ) is a poor prognostic feature in adult acute lymphoblastic leukemia (ALL). Allogenic hematopoietic stem cell transplantation in first complete remission (CR1) is recommended. There is limited literature on the role of consolidation autologous stem cell transplantation (ASCT). This study was undertaken to assess the potential of consolidation ASCT in CR1 in adults with Ph + ALL.
Objectives The aim of this study was to analyze the safety and efficacy of ASCT in CR1 in adults with Ph + ALL.
Materials and Methods Adult patients diagnosed with Ph + ALL who underwent ASCT in CR1 after modified ALL-BFM95 protocol from 2015 to 2017 were included. Patients who achieved major molecular response or better were considered for ASCT with cyclophosphamide-total body irradiation regimen and peripheral blood stem cells infused on day 0. Toxicities as per Common Terminology Criteria for Adverse Event v4.0, disease-free survival (DFS), and overall survival (OS) were assessed. Inclusion criteria: Following patients were included—patients aged 18 years and above diagnosed with Ph + ALL; patients receiving BFM-95 induction chemotherapy protocol; patients who achieved CR after induction therapy; nonavailability of human leukocyte antigen match from a matched sibling donor or matched unrelated donor. Exclusion criteria: Patients not willing or unfit for ASCT and patients planned for allogenic hematopoietic stem cell transplantation were excluded.
Results Six adult patients with Ph + ALL underwent ASCT in CR1 (median age: 23 [range: 19–36] years, five patients were males [83%]). Imatinib was started at a median of 11 days from the start of induction IA (range: 10–21). Five patients achieved morphological CR after induction 1A and, one patient at the end of induction 1B. The median time to ASCT (from diagnosis) was 8 months (range: 6.4–13). All the six patients had disease relapse and died due to progressive ALL. The median DFS and OS were 19.2 months and 23.3 months, respectively.
Conclusion Consolidation ASCT yielded poor outcomes in this study. There was a significant delay from diagnosis to ASCT, which might have impacted the results.
Keywords
Philadelphia chromosome - autologous stem cell transplantation - acute lymphoblastic leukemia - consolidation therapyAuthor's Contributions
All co-authors have reviewed the manuscript and have contributed substantially to the present study.
Ethics Approval
As this study was a retrospective analysis of patients with Ph + ALL who underwent ASCT between 2015 and 2017, IEC approval was not required per institutional policy. An IEC waiver form was obtained for the same.
Consent
Informed consent was obtained from all individual participants included in the study.
Publication History
Article published online:
17 April 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
Abstract
Introduction Philadelphia chromosome positivity (Ph + ) is a poor prognostic feature in adult acute lymphoblastic leukemia (ALL). Allogenic hematopoietic stem cell transplantation in first complete remission (CR1) is recommended. There is limited literature on the role of consolidation autologous stem cell transplantation (ASCT). This study was undertaken to assess the potential of consolidation ASCT in CR1 in adults with Ph + ALL.
Objectives The aim of this study was to analyze the safety and efficacy of ASCT in CR1 in adults with Ph + ALL.
Materials and Methods Adult patients diagnosed with Ph + ALL who underwent ASCT in CR1 after modified ALL-BFM95 protocol from 2015 to 2017 were included. Patients who achieved major molecular response or better were considered for ASCT with cyclophosphamide-total body irradiation regimen and peripheral blood stem cells infused on day 0. Toxicities as per Common Terminology Criteria for Adverse Event v4.0, disease-free survival (DFS), and overall survival (OS) were assessed. Inclusion criteria: Following patients were included—patients aged 18 years and above diagnosed with Ph + ALL; patients receiving BFM-95 induction chemotherapy protocol; patients who achieved CR after induction therapy; nonavailability of human leukocyte antigen match from a matched sibling donor or matched unrelated donor. Exclusion criteria: Patients not willing or unfit for ASCT and patients planned for allogenic hematopoietic stem cell transplantation were excluded.
Results Six adult patients with Ph + ALL underwent ASCT in CR1 (median age: 23 [range: 19–36] years, five patients were males [83%]). Imatinib was started at a median of 11 days from the start of induction IA (range: 10–21). Five patients achieved morphological CR after induction 1A and, one patient at the end of induction 1B. The median time to ASCT (from diagnosis) was 8 months (range: 6.4–13). All the six patients had disease relapse and died due to progressive ALL. The median DFS and OS were 19.2 months and 23.3 months, respectively.
Conclusion Consolidation ASCT yielded poor outcomes in this study. There was a significant delay from diagnosis to ASCT, which might have impacted the results.
Keywords
Philadelphia chromosome - autologous stem cell transplantation - acute lymphoblastic leukemia - consolidation therapyIntroduction
The most common cytogenetic abnormality associated with adult acute lymphoblastic leukemia (ALL) is the Philadelphia chromosome, and it is seen in 20 to 30% of all adult ALL.[1] [2] Philadelphia chromosome is due to the reciprocal translocation between long arms of chromosome 9 and 22: the Abelson (ABL1) oncogene on chromosome 9 translocate to the breakpoint cluster region (BCR) oncogene on chromosome 22, resulting in a fusion oncoprotein with constitutive tyrosine kinase activity leading to excessive proliferation of leukemic cells.[3]
Ph + ALL carries a poor prognosis in adult patients. However, the incorporation of tyrosine kinase inhibitors (TKIs) with standard chemotherapy has significantly improved outcomes.[4] The treatment of choice remains allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1).[4] However, in patients who lack a human leukocyte antigen (HLA) match or in older patients, several reports suggest the advantage of consolidation autologous stem cell transplantation (ASCT) in Ph + ALL.[5] [6] [7] The absence of the graft-versus-leukemia effect is a major drawback with ASCT.
Data on adult Ph + ALL outcomes from India are scarce. In a multicenter study by the Indian Acute Leukemia Research Database (INwARD) of the Hematology Cancer Consortium, Ph + ALL was diagnosed in 17% of all adolescent and young adult (AYA) ALL patients (15–29 years).10 The 2-year event-free survival among patients with Ph + ALL was 48 versus 59% for patients with Ph-ALL (p = 0.01).[8]
The present study was undertaken to analyze the real-world outcomes of ASCT in CR1 in adult patients with Ph + ALL due to the lower uptake of consolidation allo-HCT in India due to various socio-economic factors.
Materials and Methods
In 2015, based on the GRAALL study,[5] after obtaining a written informed consent, we started offering ASCT in adult patients with Ph + ALL in CR1. Ph + ALL was confirmed by the demonstration of BCR-ABL by qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments.
Ethics Committee Approval
As this study was a retrospective analysis of patients with Ph + ALL who underwent ASCT between 2015 and 2017, Institutional Ethics Committee approval (IEC) was not required. However, an IEC waiver was obtained: IEC Waiver form- Ref No-IEC/2021/Dec01. The patients received standard chemotherapy as per the modified Berlin-Frankfurt-Munster-95 (ALL-BFM95) protocol.[9] Imatinib was incorporated along with standard chemotherapy as soon as BCR-ABL by qualitative RT-PCR was positive.
Inclusion Criteria
Following patients were included for the study: Patients aged between 18 and 50 years and above diagnosed with Ph + ALL; patients receiving ALL-BFM95 induction chemotherapy protocol; patients who achieved CR after induction therapy; nonavailability of HLA match from a matched sibling donor or matched unrelated donor.
Exclusion Criteria
Patients not willing or unfit for ASCT and patients planned for allo-HSCT were excluded.
Induction IA consisted of prednisolone (60 mg/m2, D1–D28), vincristine (1.5 mg/m2, D8, D15, D22, D29), without daunorubicin and L-asparaginase and three doses of intrathecal (IT) methotrexate; IT was started after clearance of blasts in peripheral blood. Bone marrow studies were performed after the end of IA.
The second induction (IB) from day 34 to day 61 comprised of tablet 6-mercaptopurine (60 mg/m2, D34- D61), injection cyclophosphamide (1gm/m2 D34, D61), injection cytarabine arabinoside (75 mg/m2, 4 blocks) and two more doses of IT methotrexate. BCR- ABL by quantitative RT-PCR was done at the end of IB. Morphological CR was defined as less than 5% blasts in the bone marrow aspirate smear with an absence of blasts in the peripheral smear with no extramedullary disease and transfusion independence. If the patient was not in CR after the end of IA, bone marrow studies were repeated at the end of IB. Bone marrow was not assessed for minimal residual disease (MRD) as it was not available at our center during the study period.
Major molecular response (MMR) was defined as BCR-ABL transcripts less than or equal to 0.1% by quantitative RT-PCR. Eligible patients were then consolidated with ASCT in CR1.
Cyclophosphamide-total body irradiation (Cy-TBI): cyclophosphamide 60 mg/kg for 2 days and TBI 2Gy twice daily for 3 days were used as a conditioning regimen. Cy-TBI conditioning was chosen because of its myeloablative and adequate immunosuppressive properties ensuring an adequate antileukemic effect, also ensuring homogenous dose distribution to the whole body, including sanctuary sites such as the central nervous system (CNS) and testicles.[5] [7]
Stem cells were mobilized from the peripheral blood after priming with granulocyte colony stimulating factor (G-CSF) 10 µg/kg daily for 5 days. Plerixafor 0.24 mg/kg was given 10 to 12 hours before the apheresis. The apheresis was performed on day 5 of G-CSF. Engraftment was defined as peripheral blood neutrophil count more than 500/mm3 for 3 consecutive days and platelet count more than 20,000/mm3 for at least 7 days independent from platelet transfusion. All the patients were restarted on imatinib post-transplant upon engraftment.
Statistical Analysis
ASCT with Cy-TBI conditioning-related toxicities, disease-free survival (DFS), and overall survival (OS) were assessed. Toxicities were assessed as per Common Terminology Criteria for Adverse Event v4.0.[10] DFS was defined as the time to relapse of leukemia or death from the date of morphological CR. OS was defined as the time from diagnosis to death. OS after relapse was calculated as the time from disease relapse to death. Data were retrieved from electronic case records or case files, compiled, and analyzed using Microsoft Excel 2016.
Results
Seven patients were screened for the study, and six were included (refused ASCT-1). Six adult patients with Ph + ALL underwent ASCT in CR1 between 2015 and 2017 ([Table 1]). The median age of the study group was 23 years (range: 19–36); five out of six were males (83%). p190 BCR-ABL transcript by qualitative RT-PCR was detected in all the six patients. Conventional cytogenetics revealed t(9;22) in two patients (33%) and normal karyotype in the other four patients. CSF study was performed on day 8 after clearance of peripheral blood blasts. None of the patients had CNS disease. The median duration of starting imatinib was D + 11 of IA (range: 10–21). All the patients were compliant with imatinib. Five patients achieved morphological CR after IA and one patient at the end of IB. All the patients achieved MMR or better before ASCT. Among the six patients, five underwent ASCT during consolidation and one during second maintenance. Delay in ASCT was due to prolonged transplant waiting period due to immediate bed nonavailability.
Parameter |
Case 1 |
Case 2 |
Case 3 |
Case 4 |
Case 5 |
Case 6 |
---|---|---|---|---|---|---|
Day of starting imatinib during IA |
D + 11 |
D + 21 |
D + 10 |
D + 12 |
D + 11 |
D + 11 |
Initial dose of imatinib |
400 mg o.d. escalated to 600 mg o.d. |
400 mg o.d. escalated to 800 mg o.d. |
400 mg o.d. |
400 mg o.d. |
400 mg o.d. escalated to 600 mg o.d. |
400 mg o.d. escalated to 600 mg o.d. |
End of induction (IA) BM status |
CR |
Not in CR (CR achieved after IB) |
CR |
CR |
CR |
CR |
BM prior to ASCT |
CR |
CR |
CR |
CR |
CR |
CR |
Quantitative BCR-ABL prior to ASCT |
0.03% |
Undetectable |
Undetectable |
Undetectable |
Undetectable |
0.06% |
Phase of treatment during which ASCT was performed |
Consolidation |
2nd maintenance |
Consolidation |
Consolidation |
Consolidation |
Consolidation |
Time to ASCT from diagnosis (mo) |
6.4 |
13 |
8.5 |
8.4 |
5.9 |
8 |
Day of starting imatinib post-transplant and dose |
D + 32 600 mg o.d. |
D + 33 400 mg o.d. escalated to 600mg o.d. |
D + 42 400 mg o.d. |
D + 36 600 mg o.d. |
D + 33 600 mg o.d. |
D + 34 600 mg o.d. |
Quantitative BCR-ABL post-ASCT |
N/D |
N/D |
Undetectable (+8 mo) |
Undetectable (+9 mo) |
Undetectable (+8 mo) |
N/D |
DFS (in mo) |
8.9 |
20.5 |
59.1 |
23.2 |
17.9 |
10.3 |
Type of relapse |
Medullary |
Isolated CNS |
Isolated CNS |
Medullary |
Medullary |
Medullary |
2nd line TKI and dose at relapse |
Nil |
Dasatinib 50 mg o.d. |
Dasatinib 50 mg o.d. |
Dasatinib 50 mg o.d. |
Nil |
Dasatinib 50 mg o.d. |
OS (in mo) |
13.2 |
32.8 |
68.8 |
44.4 |
20.3 |
14.8 |
OS after relapse (in mo) |
3 |
11 |
8.5 |
5 |
1.3 |
3.4 |
Parameter |
Case 1 |
Case 2 |
Case 3 |
Case 4 |
Case 5 |
Case 6 |
---|---|---|---|---|---|---|
Febrile neutropenia |
Grade 3 |
Grade 3 |
Grade 3 |
Grade 3 |
Grade 3 |
Grade 3 |
Infections |
Nil |
CLABSI- Coagulase-negative staphylococcus aureus |
Nil |
H1N1 bronchopneumonia (not requiring oxygen or ventilatory support) |
Acute suppurative otitis media (organism not grown) |
Nil |
Chemotherapy-induced nausea and vomiting |
Grade 3 |
Grade 2 |
Grade 3 |
Grade 3 |
Grade 2 |
Grade 2 |
Mucositis oral |
Grade 3 |
Grade 2 |
Grade 2 |
Grade 2 |
Grade 2 |
Grade 2 |
Diarrhea |
Nil |
Grade 2 |
Nil |
Grade 2 |
Grade 2 |
Grade 2 |
Variable |
GRAAPH 2003 (5) |
CALGB 10001(Alliance) (6) |
EBMT (7) |
Present study |
---|---|---|---|---|
Sample size |
10 |
19 |
67 |
6 |
Conditioning regimen |
Cy-TBI |
Ara-c/VP 16-TBI |
TBI based- 64% Cy-TBI Flu-TBI Chemotherapy-based-(34%) Bu-Cy Bu-Flu Bu-Mel |
Cy-TBI |
TRM |
0 |
1(5%) |
1(1.49%) |
0 |
MRD assessment |
Yes |
Yes |
Variable |
No |
References
- Secker-Walker LM, Prentice HG, Durrant J, Richards S, Hall E, Harrison G. MRC Adult Leukaemia Working Party. Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA. Br J Haematol 1997; 96 (03) 601-610
- Mrózek K, Harper DP, Aplan PD. Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2009; 23 (05) 991-1010 , v
- Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2010; 116 (18) 3409-3417
- Rowe JM, Buck G, Burnett AK. et al; ECOG, MRC/NCRI Adult Leukemia Working Party. 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; 106 (12) 3760-3767
- Tanguy-Schmidt A, Rousselot P, Chalandon Y. et al. Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant 2013; 19 (01) 150-155
- Wetzler M, Watson D, Stock W. et al. Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance). Haematologica 2014; 99 (01) 111-115
- Giebel S, Labopin M, Gorin NC. et al. Improving results of autologous stem cell transplantation for Philadelphia-positive acute lymphoblastic leukaemia in the era of tyrosine kinase inhibitors: a report from the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Eur J Cancer 2014; 50 (02) 411-417
- Ganesan P, Jain H, Bagal B. et al. Outcomes in adolescent and young adult acute lymphoblastic leukaemia: a report from the Indian Acute Leukaemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC). Br J Haematol 2021; 193 (01) e1-e4
- Liang SY. Monitoring MRD guided treatment outcome of adult patients with acute lymphoblastic leukemia using ALL-BFM95 based protocol. Blood 2017; 130 (Suppl. 01) 5040-5040
-
Common Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP [Internet] [cited 2023 Jan 30]. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40
- Jain P, Korula A, Deshpande P. et al. Adult acute lymphoblastic leukemia: limitations of intensification of therapy in a developing country. J Glob Oncol 2018; 4: 1-12
Address for correspondence
Nikita Mehra, MD, DMDepartment of Medical Oncology, Department of Molecular Oncology, Cancer Institute (WIA)Dr. S. Krishnamurthy Campus, 38 Sardar Patel Road, Chennai, Tamil Nadu, 600036IndiaPublication History
Article published online:
17 April 2023© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
References
- Secker-Walker LM, Prentice HG, Durrant J, Richards S, Hall E, Harrison G. MRC Adult Leukaemia Working Party. Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA. Br J Haematol 1997; 96 (03) 601-610
- Mrózek K, Harper DP, Aplan PD. Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2009; 23 (05) 991-1010 , v
- Fielding AK. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2010; 116 (18) 3409-3417
- Rowe JM, Buck G, Burnett AK. et al; ECOG, MRC/NCRI Adult Leukemia Working Party. 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; 106 (12) 3760-3767
- Tanguy-Schmidt A, Rousselot P, Chalandon Y. et al. Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant 2013; 19 (01) 150-155
- Wetzler M, Watson D, Stock W. et al. Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance). Haematologica 2014; 99 (01) 111-115
- Giebel S, Labopin M, Gorin NC. et al. Improving results of autologous stem cell transplantation for Philadelphia-positive acute lymphoblastic leukaemia in the era of tyrosine kinase inhibitors: a report from the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Eur J Cancer 2014; 50 (02) 411-417
- Ganesan P, Jain H, Bagal B. et al. Outcomes in adolescent and young adult acute lymphoblastic leukaemia: a report from the Indian Acute Leukaemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC). Br J Haematol 2021; 193 (01) e1-e4
- Liang SY. Monitoring MRD guided treatment outcome of adult patients with acute lymphoblastic leukemia using ALL-BFM95 based protocol. Blood 2017; 130 (Suppl. 01) 5040-5040
-
Common Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP [Internet] [cited 2023 Jan 30]. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40
- Jain P, Korula A, Deshpande P. et al. Adult acute lymphoblastic leukemia: limitations of intensification of therapy in a developing country. J Glob Oncol 2018; 4: 1-12