Volume 125, Issue 16 p. 2810-2817
Original Article
Free Access

Incidence and outcome after first molecular versus overt recurrence in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia included in the ALL Ph08 trial from the Spanish PETHEMA Group

Josep-Maria Ribera MD, PhD

Corresponding Author

Josep-Maria Ribera MD, PhD

Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain

Corresponding author: Josep-Maria Ribera, MD, PhD, Department of Clinical Hematology, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Universitat Autonoma de Barcelona, Spain; [email protected]

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Olga García MD

Olga García MD

Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain

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María-José Moreno MD

María-José Moreno MD

Department of Hematology, Hospital of the Virgen de la Victoria, Malaga, Spain

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Pere Barba MD

Pere Barba MD

Department of Hematology, Vall d’Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain

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Irene García-Cadenas MD

Irene García-Cadenas MD

Department of Hematology, Hospital of Sant Pau, Barcelona, Spain

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Santiago Mercadal MD

Santiago Mercadal MD

Department of Hematology, ICO-Hospital Duran i Reynals, L’Hospitalet de Llobregat, Catalonia, Spain

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Pau Montesinos MD

Pau Montesinos MD

Department of Hematology, Le Fe University and Polytechnic Hospital, Valencia, Spain

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Manuel Barrios MD

Manuel Barrios MD

Department of Hematology, Carlos Haya Hospital, Malaga, Spain

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José González-Campos MD

José González-Campos MD

Department of Hematology, Virgen del Rocio University Hospital, Seville, Spain

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Daniel Martínez-Carballeira MD

Daniel Martínez-Carballeira MD

Department of Hematology, Central Hospital of Asturias, Oviedo, Spain

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Cristina Gil MD

Cristina Gil MD

Department of Hematology, General University Hospital of Alicante, Alicante, Spain

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Jordi Ribera PhD

Jordi Ribera PhD

Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain

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Susana Vives MD

Susana Vives MD

Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain

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Andrés Novo MD

Andrés Novo MD

Department of Hematology, Son Espases Hospital, Palma de Mallorca, Spain

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Marta Cervera MD

Marta Cervera MD

Department of Hematology, ICO-Hospital Joan XXIII, Tarragona, Spain

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Josefina Serrano MD

Josefina Serrano MD

Department of Hematology, Reina Sofia Hospital, Cordoba, Spain

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Esperanza Lavilla MD

Esperanza Lavilla MD

Department of Hematology, Lucus Augusti Hospital, Lugo, Spain

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Eugenia Abella MD

Eugenia Abella MD

Department of Hematology, del Mar Hospital, Barcelona, Spain

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Mar Tormo MD

Mar Tormo MD

Department of Hematology, Clinical Hospital, Valencia, Spain

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María-Luz Amigo MD

María-Luz Amigo MD

Department of Hematology, Morales Meseguer University General Hospital, Murcia, Spain

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María-Teresa Artola MD

María-Teresa Artola MD

Department of Hematology, Donostia University Hospital, San Sebastian, Spain

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Eulalia Genescà PhD

Eulalia Genescà PhD

Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain

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Pilar Bravo MD

Pilar Bravo MD

Department of Hematology, Fuenlabrada University Hospital, Madrid, Spain

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Daniel García-Belmonte MD

Daniel García-Belmonte MD

Department of Hematology, La Zarzuela Hospital, Madrid, Spain

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Antoni García-Guiñón MD

Antoni García-Guiñón MD

Department of Hematology, Arnau de Vilanova Hospital, Lleida, Spain

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Jesús-María Hernández-Rivas MD

Jesús-María Hernández-Rivas MD

Department of Hematology, University Hospital of Salamanca, Salamanca, Spain

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Evarist Feliu MD

Evarist Feliu MD

Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain

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on behalf of the PETHEMA Group of the Spanish Society of Hematology

on behalf of the PETHEMA Group of the Spanish Society of Hematology

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First published: 23 April 2019
Citations: 13
Presented at the 23rd Congress of the European Hematology Association; June 14-17, 2018; Stockholm, Sweden.
We thank the physicians from the following hospitals for their participation in the study: ICO Badalona-Hospital Germans Trias i Pujol (Badalona, Spain); Hospital of the Virgen de la Victoria (Malaga, Spain); Vall d’Hebron University Hospital (Barcelona, Spain); Sant Pau Hospital (Barcelona, Spain); ICO-Hospital Duran i Reynals (L’Hospitalet de Llobregat, Catalonia, Spain); Le Fe University and Polytechnic Hospital (Valencia, Spain); Carlos Haya Hospital (Malaga, Spain); Virgen del Rocio University Hospital (Seville, Spain); Central Hospital of Asturias (Oviedo, Spain); General University Hospital of Alicante (Alicante, Spain); Son Espases Hospital (Palma de Mallorca, Spain); ICO-Hospital Joan XXIII (Tarragona, Spain); Reina Sofía Hospital (Cordoba, Spain); Lucus Augusti Hospital (Lugo, Spain); del Mar Hospital (Barcelona, Spain); Clinical Hospital (Valencia, Spain); Morales Meseguer University General Hospital (Murcia, Spain); Donostia University Hospital (San Sebastian, Spain); Fuenlabrada University Hospital (Madrid, Spain); La Zarzuela Hospital (Madrid, Spain); Arnau de Vilanova Hospital (Lleida, Spain); and University Hospital of Salamanca (Salamanca, Spain).

Abstract

Background

Disease recurrence occurs in 20% to 40% of adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) who are treated with chemotherapy and tyrosine kinase inhibitors (TKIs). In the current study, the authors report the incidence, treatment, and outcome after first disease recurrence in young and older adults treated in the ALL Ph08 trial (ClinicalTrials.gov identifier NCT01491763).

Methods

Patients aged 18 to 55 years with de novo Ph+ ALL were treated with imatinib concurrently with standard-dose induction and consolidation therapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) when possible. In patients with first disease recurrence, the authors analyzed the type of recurrence, timing, location, presence of kinase domain mutations, type of treatment, and outcomes.

Results

Of the 125 patients, 28 patients (22%) developed disease recurrence before (4 patients) or after (24 patients) HSCT, with the recurrences being molecular in 11 patients (39%) and overt in 17 patients (61%). T315I was the most common mutation noted at the time of disease recurrence. Change in TKI was the most frequent treatment for patients with molecular disease recurrence whereas rescue chemotherapy and TKI change followed by second allo-HSCT when possible were performed for the most part in patients with overt disease recurrence. A total of 20 patients (71%) achieved response. The median disease-free survival (DFS) and overall survival (OS) were 8.5 months and 15.3 months, respectively. A trend for better DFS and OS was observed in patients with molecular recurrence compared with those with overt recurrence (median of 16.9 months vs 6.3 months [= .05] and 28.7 months vs 11.5 months [= .05] for DFS and OS, respectively).

Conclusions

Disease recurrence was frequent in young and older adults with Ph+ ALL who were treated with imatinib and chemotherapy with HSCT. Although the majority of patients responded to rescue therapy, their outcomes were poor, especially with regard to overt disease recurrence.

Introduction

The current standard of care for adult patients with de novo Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) consists of induction therapy with conventional or attenuated chemotherapy in concurrent combination with BCR-ABL1 protein–specific tyrosine kinase inhibitors (TKIs).1-3 Greater than 90% of patients achieve complete remission (CR), with eligible patients generally proceeding to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after a consolidation phase including chemotherapy and TKIs.3-5 Despite these promising results, disease recurrence occurs in a percentage of adult patients, ranging from 20% to 30% in young adults to >60% in elderly patients, and remains challenging to treat.6 These recurrences are commonly associated with mutations in the kinase domain of the BCR-ABL1 oncogene that confer resistance to TKI,6-8 with T315I being the most frequent mutation. There is substantial variability in current clinical practice in the therapeutic approaches for patients with recurrences, ranging from a standard approach with TKIs combined or not with chemotherapy to immunological therapies with either monoclonal antibodies or chimeric antigen receptor (CAR) T cells, followed or not by allo-HSCT.3, 9, 10 To the authors’ knowledge, there is no definitive evidence of sustained response or long-term survival for patients with Ph+ ALL who present with disease recurrence, with the overall survival (OS) after recurrence ranging from approximately 4 to 10 months.

The objective of the current study was to report the incidence, treatment, and outcome after first disease recurrence in young and older adults (aged 18-55 years) from the Spanish PETHEMA (Programa Espanol de Tratamientos en Hematologia) Group who were treated according to the prospective ALL Ph08 trial.

Materials and Methods

Patients aged 18 to 55 years from the Spanish PETHEMA Group who were diagnosed with de novo Ph+ ALL were included in the ongoing ALL Ph08 trial (ClinicalTrials.gov identifier NCT01491763) between 2008 and 2018. The study was approved by the institutional review board of the Hospital Germans Trias i Pujol. The preliminary results of the ALL Ph08 protocol have been published elsewhere.11, 12 Induction therapy consisted of vincristine, daunorubicin, prednisone, and imatinib (from day 1 until the beginning of the consolidation). Consolidation consisted of mercaptopurine, high-dose methotrexate, etoposide, high-dose cytarabine, and imatinib. Triple intrathecal therapy (methotrexate, cytarabine, and hydrocortisone) was used for central nervous system prophylaxis. In patients with detectable minimal residual disease (MRD) after consolidation, imatinib was changed to dasatinib until the HSCT admission to strengthen MRD response. allo-HSCT from a matched-related donor, matched-unrelated donor, unrelated cord blood, or haploidentical donor (according to center decision) was performed after consolidation when possible. The myeloablative conditioning regimen included cyclophosphamide and fractionated total body irradiation, and the reduced conditioning regimen consisted of fludarabine and melphalan. Maintenance therapy with imatinib was scheduled for patients in whom molecular disease persisted or reappeared after allo-HSCT was performed.13 Patients who were unfit for allo-HSCT received autologous HSCT followed by maintenance therapy (methotrexate, mercaptopurine, and imatinib) for 2 years.

The BCR-ABL1/ABL ratio was evaluated by real-time quantitative polymerase chain reaction in each participating center at the end of induction, the end of consolidation/before HSCT, and periodically after HSCT (monthly in the first 6 months and every 2-3 months thereafter). A second confirmatory test was performed within the 2 weeks after the initial test in patients with borderline values (eg, BCR-ABL/ABL ratio of 0.01%-0.1%). A minimum of 10,000 copy numbers of the housekeeping gene (ABL1) was required to be considered a valid result. A mutation study was performed locally by Sanger sequencing in patients with overt disease recurrence. In patients without a mutation, no other method was performed to confirm the absence of a mutation.

CR was defined as <5% bone marrow blasts and the absence of blasts in the peripheral blood with recovery of hematopoiesis without extramedullary disease. BCR-ABL1/ABL ratios ≤0.1% or ≤0.01% (or undetectable) defined a major molecular response and complete molecular response (CMR), respectively. Molecular recurrence was defined as a BCR-ABL1/ABL ratio >0.01% in a patient with a previous CMR, and overt recurrence was considered to occur when ≥5% of blast cells were detected in bone marrow or ALL reappeared in any extramedullary site. Disease-free survival (DFS) was defined as the time from CR until disease recurrence, death, or last follow-up in CR. OS was defined as the time from diagnosis to the last follow-up or death from any cause.

Statistical Analysis

A descriptive study of the characteristics of the patients with disease recurrence was performed, and the type and response to the rescue therapy were compared according to the type of disease recurrence (molecular vs overt). The DFS and OS curves were plotted using the Kaplan-Meier method and were compared using the log-rank test. Nonrecurrence mortality and recurrence incidence were calculated using cumulative incidence rates by competing risks analysis. All P values <.05 were considered statistically significant.

Results

From 2008 to 2018, a total of 133 young and older adults (aged 18-55 years) with de novo Ph+ ALL from 44 Spanish hospitals were included in the ALL Ph08 study. Of these, 130 were valid for outcome analysis after induction (2 patients were receiving induction therapy at the time of last follow-up and 1 patient withdrew consent before initiating therapy). Supporting Figure 1 shows the flow chart of the current study. Four patients died during induction, 1 had resistant disease, and 125 patients (96%) attained CR. At the time of last follow-up, 4 patients were receiving consolidation therapy, 1 patient had died of toxicity, 2 patients abandoned the study as per patient decision, 4 patients developed disease recurrence during or after the consolidation, and 6 patients were waiting to undergo HSCT. HSCT was performed in 108 patients (103 with allo-HSCT and 5 with autologous HSCT). Transplantation-related mortality occurred in 24 patients, and 24 patients developed disease recurrence after undergoing HSCT (21 after allo-HSCT and 3 after autologous HSCT). The probabilities of DFS and OS at 5 years were 53% (95% CI, 43%-63%) and 57% (95% CI, 47%-67%), respectively (see Supporting Fig. 2).

A total of 28 patients (22%) presented with disease recurrence (before HSCT in 4 patients [14%] or after HSCT in 24 patients [86%]), 11 of which were molecular (39%) and 17 of which were overt (61%). All molecular recurrences were detected after HSCT. With a median follow-up of 3 years (range, 0.1-9.2 years) for surviving patients, the cumulative incidences of disease recurrence and treatment-related mortality were 27% (95% CI, 19%-36%) and 24% (95% CI, 16%-33%), respectively (Fig. 1). Table 1 shows the main clinical and biological characteristics of the patients with disease recurrence and Supporting Table 1 shows the comparison of baseline characteristics between patients who relapsed and those who did not. Most of the recurrences involved the bone marrow (14 patients), either isolated (12 patients) or combined with the central nervous system (2 patients). Mutation status at the time of recurrence was studied in 9 of the 17 patients with overt recurrence and in 4 of the 11 patients with molecular recurrence, with T315I (4 patients) and E255K (3 patients) mutations found to be the most frequent. Combined mutations were found in only 1 patient.

Details are in the caption following the image
Cumulative incidence of disease recurrence (CIR) and nonrecurrence mortality (NRM) among the patients included in the current study. CR, complete remission.
Table 1. Main Characteristics of the Patients in First Disease Recurrence
Characteristics at Disease Recurrence Patients N = 28
Median age (range), y 39 (17-54)
Male, no. (%) 18/28 (64)
Type of recurrence (molecular/overt) 11/17
Site of overt recurrence (n = 17) BM isolated: 12
Combined: 2a
CNS isolated: 2
Other extramedullary: 1b
Timing (before/after HSCT) 4/24c
Median Hb (range), g/L 116 (85-134)
Median WBC count (range), ×109/L 5.1 (0.97-111.4)
Median platelet count (range), ×109/L 122 (9-225)
Median BM blasts (range), % 73 (9-92)e
BCR-ABL transcripts, no. (%)e
p190 16/22 (73)
p210 5/22 (23)
p190 plus p210 1/22 (4)
Additional cytogenetic abnormalities, no. (%) 8/14 (57)
Mutation status at disease recurrence (n = 13)f
No mutation found 5 (38%)
T315I 4 (31%)
E255K 3 (23%)
Y253H, E255V, and E355G 1 (8%)
  • Abbreviations: BM, bone marrow; CNS, central nervous system; Hb, hemoglobin; HSCT, hematopoietic stem cell transplantation; WBC, white blood cell.
  • a BM and CNS in both.
  • b Testicular.
  • c All molecular recurrences occurred after HSCT.
  • d Only for those patients with BM recurrence.
  • e BCR-ABL isoform was not available for 6 patients.
  • f Molecular recurrence was noted in 4 patients: no mutation (1 patient), T315I (1 patient), and E255K (2 patients). Overt recurrence was noted in 9 patients: no mutation (4 patients); T315I (3 patients); E255K (patient 1); and compound Y253H, E255V, and E355G (1 patient).

Two patients did not receive treatment, 2 received rescue chemotherapy without a TKI, 13 received TKIs exclusively, and 11 patients were treated with TKIs and salvage chemotherapy. One patient from each group (those with molecular and overt disease recurrence) received donor lymphocyte infusions as part of rescue therapy. Two patients with overt recurrence died during rescue therapy, one patient was receiving treatment at the time of the analysis, and 12 of the remaining 14 patients (86%) achieved morphologic CR. In turn, 2 patients from the molecular recurrence group did not attain CMR after TKI therapy, 1 additional patient with early recurrence after allo-HSCT could not be evaluated because of acute grade 5 graft-versus-host disease according to the Fred Hutchinson Cancer Research Center grading system, and 8 patients attained molecular remission. Thus, molecular response was attained in 8 of 10 patients (80%) with molecular recurrence and in 9 of 10 patients (90%) with overt recurrence (molecular study was not performed in 4 patients). No relationship was found between the level of post-SCT MRD and long-term outcomes in patients with molecular recurrence. The median time between CR and molecular recurrence was 9.7 months. No differences in outcome were observed based on comparison of molecular recurrence before or after this time point (medians of DFS of 12.7 months vs 16.9 months, respectively). The median time to attain a second molecular response in patients with molecular recurrence was 1.8 months (range, 1.2-3.3 months), with no relationship observed between the speed of molecular response attainment and outcome (taking 2 months as a cutoff value). A second allo-HSCT was performed in 7 patients (all from the group with overt recurrence). At the time of last follow-up, 5 of these patients developed disease recurrence (4 died and 1 patient was alive with active disease at the time of last follow-up), 1 patient died due to transplantation complications, and 1 patient was alive in molecular remission. At the time of the analysis, 12 patients developed disease recurrence and 17 patients died. Table 2 shows the results of therapy according to the type of recurrence. As demonstrated, patients with molecular recurrence were treated with TKIs only (increased imatinib dose in 2 patients and a change to dasatinib in 9 patients), whereas patients with overt clinical recurrence preferentially received TKIs combined with rescue chemotherapy (11 patients), followed by a second allo-HSCT when possible (7 patients). The median DFS of the series was 8.5 months (95% CI, 2.1-14.9 months), and the median OS was 15.3 months (95% CI, 8.0-22.6 months) (Figs. 2A and 2B). A trend toward better DFS and OS was observed in patients with molecular disease recurrence compared with those with systemic disease recurrence (medians of 16.9 months [95% CI, noncalculable] vs 6.3 months [95% CI, 2.1-10.4 months] [= .05] and 28.7 months [95% CI, noncalculable] vs 11.5 months [95% CI, 8.5-14.5 months] [= .05] for DFS and OS, respectively) (Figs. 3A and 3B).

Table 2. Type and Response to Rescue Therapy According to the Type of Disease Recurrence
Molecular Recurrence N = 11 Overt Recurrence N = 17
Type of treatment Increase imatinib dose (n = 2) TKI plus intensive chemotherapy (n = 11)a, b
Change to dasatinib (n = 9)a Intensive chemotherapy without TKI (n = 2)
Change TKI without salvage
chemotherapy (n = 2)c
No treatment (n = 2)
Morphologic CR 12/14 (86%)d
Molecular CR 8/10e 9/10
Second HSCT in CR2 0 7
Disease recurrence 3/8 9/12
Median DFS (95% CI), mo 16.9 (NE) 6.3 (2.1-10.4)
Death 5/11 12/17
Median OS (95% CI), mo 28.7 (NE) 11.5 (8.5-14.5)
  • Abbreviations: CR, complete remission; CR2, second complete remission; DFS, disease-free survival; HSCT, hematopoietic stem cell transplantation; NE, not estimable; OS, overall survival; TKI, tyrosine kinase inhibitor.
  • a One patient from each group received donor lymphocyte infusions concomitant with rescue therapy.
  • b Increased imatinib dose (1 patient), dasatinib (5 patients), nilotinib (1 patient), and ponatinib (4 patients).
  • c Nilotinib (1 patient) and dasatinib (1 patient).
  • d One patient was receiving treatment and 2 patients died during rescue therapy.
  • e One patient was not evaluated.
Details are in the caption following the image
Probabilities of (A) disease-free survival (DFS) and (B) overall survival (OS) among patients who developed disease recurrence. CR, complete remission.
Details are in the caption following the image
Probabilities of (A) disease-free survival (DFS) and (B) overall survival (OS) according to the type of disease recurrence (molecular vs overt). CR indicates complete remission; NA, not available, NR, not reported.

Discussion

The results of the current study demonstrated a cumulative incidence rate of 27% in young and older patients with Ph+ ALL who were treated with the concurrent combination of imatinib and standard chemotherapy followed by allo-HSCT when possible. The majority of the disease recurrences occurred after HSCT and were detected molecularly in approximately 40% of the patients. The therapeutic approach was different in patients with molecular and overt recurrences, being exclusively based on increased dose or change in the TKI in the former and on chemotherapy plus TKI followed by a second HSCT if possible in the latter. Despite this more intensive approach, the outcome was poorer in patients with overt disease recurrence.

To the best of our knowledge, there is no standard approach in routine clinical practice for the treatment of first disease recurrence in patients with Ph+ ALL, and the current recommendation is to try to include these patients in clinical trials with more potent and extended-spectrum TKIs or with immunological approaches with monoclonal antibodies or CAR T-cell programs.14 In addition, preliminary results have shown that the combination of TKIs and blinatumomab is feasible and effective in adult patients with recurrent or refractory (R/R) Ph+ ALL.15

There are scarce studies focused on the outcome of patients with Ph+ ALL in first disease recurrence. A recently reported series from The University of Texas MD Anderson Cancer Center included 57 patients with first overt recurrence among 233 patients with Ph+ ALL who were treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) combined with either imatinib, dasatinib, or ponatinib,16 and described an incidence (24%) similar to that found in the current study (22%). The majority of patients (84%) achieved a second CR but despite this, the duration of CR and the OS (2-year probability of 20%) remained poor, as occurred in the current series. Allo-HSCT did not appear to improve survival, mainly due to a high transplantation-related mortality rate (53%). On multivariate analysis, elevated serum lactate dehydrogenase levels at the time of disease recurrence and the use of imatinib or no TKI in rescue treatment were associated with poor outcome, and the achievement of a major molecular response at the time of second CR predicted improved recurrence-free survival and OS.

The outcome for patients in the current study with overt disease recurrence is not unexpected and is in agreement with published data. It would be more interesting to focus on the patients with molecular recurrence because some of them fared reasonably well, and for whom there is no standard approach. All of these instances of disease recurrence were detected after allo-HSCT, with the median time between CR and molecular recurrence of 9.7 months. The therapeutic approach was based exclusively on increasing the dose of imatinib or, more frequently, changing to a second-generation TKI (dasatinib) with a reasonably good molecular remission rate (80%), achieved within a short period of time (median, 1.8 months). Despite this, 3 of 8 patients experienced a second recurrence. This points to the need to use more effective therapeutic approaches in patients with molecular recurrence.

The first approach would be the use of more potent and extended-spectrum TKIs such as ponatinib. Ponatinib has shown activity as a single drug in patients with R/R Ph+ ALL, with a major hematologic response rate of 41%, a median duration of 3.2 months, and major and complete cytogenetic responses of 47% and 38%, respectively, according to the updated data from the PACE trial.17 Because these promising outcomes were observed in patients who had refractory disease or were in overt recurrence, it appears logical to anticipate better results in patients with first molecular recurrence.

The second possible approach is to use immunotherapy with monoclonal antibodies, especially blinatumomab. The ALCANTARA (A Phase 2 Single Arm, Multicenter Trial to Evaluate the Efficacy of the BiTE Antibody Blinatumomab in Adult Subjects With Relapsed/Refractory Philadelphia Positive B-precursor Acute Lymphoblastic Leukemia) phase 2 study analyzed the activity of blinatumomab as a single drug in adult patients who had developed disease recurrence after or were refractory to at least 1 second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib.9 The rate of CR or CR with incomplete hematological recovery during the first 2 cycles was 36%, with 88% of CMRs noted among patients with CR and/or CR with incomplete hematological recovery, and a median recurrence-free survival and OS of 6.7 months and 7.1 months, respectively. In turn, a small number of patients with R/R Ph+ ALL were included in the randomized INO-VATE (INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy) trial, with a CR rate of 78% noted in the patients randomized to the inotuzumab arm.18 Once again, both trials included patients with a more advanced status of disease recurrence, and the expected higher activity of blinatumomab or inotuzumab in patients in first molecular recurrence remains to be proven.

A third possible approach could be the combination of a TKI and immunotherapy, but to the best of our knowledge experience with this combination is only preliminary and limited to patients with overt R/R status.15 The possibility of performing allo-HSCT is attractive for patients with Ph+ ALL with low tumor burden at the time of first recurrence. However, all patients in the current study with first molecular recurrence had previously undergone transplantation and the majority of molecular recurrences occurred early (median time from CR to molecular recurrence of only 9.7 months), a feature that anticipates a high probability of transplantation-related mortality in the second allo-HSCT. Finally, the experience with CAR T cells including information regarding Ph chromosome status is limited and, once again, focused on patients with overt R/R status.10

Some specific points should be considered in the current study. First, the management of the patients with Ph+ ALL in first recurrence was based on current clinical practice outside phase 2 or 3 clinical trials. Second, the current study included only young and older adults aged 18 to 55 years. Third, molecular recurrences together with overt recurrences were considered, although they were analyzed separately by the type of therapy and outcome. Fourth, imatinib was the only TKI given in combination with chemotherapy as first-line therapy. Finally, all fit patients in first CR were scheduled to undergo HSCT, preferentially allogeneic HSCT, with a high percentage of patients actually undergoing transplantation. With the exception of the study from The University of Texas MD Anderson Cancer Center,16 we believe it is impossible to perform direct comparisons with the data from the aforementioned clinical trials with new drugs; the prior studies included patients with R/R Ph+ ALL who were unselected by age and more advanced recurrences generally were noted in a significant percentage of cases. In contrast to what has been examined with blinatumomab19 and inotuzumab18 in patients with Ph-negative ALL, to the best of our knowledge, there are no randomized studies to date comparing the current clinical practice with the new approaches in clinical trials in patients with R/R Ph+ ALL (except for a small number of Ph+ ALL cases included in the INO-VATE trial18). In addition, no information regarding the activity of these drugs is available for patients with Ph+ ALL in molecular recurrence. In our opinion, the results of the current study could provide valuable information for comparison with those trials currently ongoing that include novel agents alone or in combination in Ph+ ALL patients in first recurrence.

Funding Support

Supported in part by grants RD12/0036/0029 (Cancer Cooperative Research Thematic Network/Spanish Federation of Rare Diseases [RTICC/FEDER), PI14/01971 FIS, Carlos III Health Institute, and SGR 288 (GRC) Spain. Pere Barba was supported by grants from the Carlos III Health Institute (FIS16/01433) and PERIS 2018-2020 from the Generalitat of Catalunya (BDNS357800).

Conflict of Interest Disclosures

Josep-Maria Ribera has served as speaker and has participated in advisory boards for Pfizer, Amgen, Shire, Ariad, and Takeda. The other authors made no disclosures.

Author Contributions

Josep-Maria Ribera designed the study, contributed to the analysis of the data, and wrote the article. Olga García analyzed the data. María-José Moreno, Pere Barba, Irene García-Cadenas, Santiago Mercadal, Pau Montesinos, Manuel Barrios, José González-Campos, Daniel Martínez-Carballeira, Cristina Gil, Jordi Ribera, Susana Vives, Andrés Novo, Marta Cervera, Josefina Serrano, Esperanza Lavilla, Eugenia Abella, Mar Tormo, María-Luz Amigo, María-Teresa Artola, Eulalia Genescà, Pilar Bravo, Daniel García-Belmonte, Antoni García-Guiñón, Jesús-María Hernández-Rivas, and Evarist Feliu qualified for autorship according to the World Association of Medical Editors (WAME) criteria, reported the patients, and followed them clinically.