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INTRODUCTION
Chronic myelogenous leukemia (CML) is a neoplastic proliferation of the granulocytic series, predominantly; abnormalities are observed in the red series and platelets, suggesting that the disease originates in stem cells or pluripotent cells. The disease has been classically associated with a chromosomal abnormality known as the Philadelphia chromosome (Ph1). A correct diagnosis requires the demonstration of Ph1 (+) through conventional karyotyping, fluorescent in situ hybridization (FISH), or by establishing the presence of the BCR-ABL hybrid gene by polymerase chain reaction (PCR) techniques1.
CML in Mexico is less frequent than acute leukemia but more common than chronic lymphocytic leukemia1. Globally, the incidence of CML is 1-1.5/100,000 inhabitants. Its incidence in the United States is 1-2 cases/100 000 inhabitants/year and it accounts for 15% of all adult leukemias. In Mexico, approximately 10% of all leukemias are CML. The mortality rate of this disease is 3/100,000 inhabitants1,2, it predominates in adults between the ages of 40-60 years, and it is more frequent in men than in women1,3.
Before the year 2000, CML treatment was based on the use of busulfan, hydroxyurea, and interferon alpha4. The arrival of targeted chronic myelogenous leukemia (CML) therapy in 2001 was revolutionary5. Imatinib was the first tyrosine kinase inhibitor (TKI) approved for the management of CML as it significantly increased these patients´ overall survival (OS)6. However, due to the high costs of TKIs, access to this highly effective therapy with associated stringent monitoring strategies has been limited in low- and middle-income countries (LMIC)5. Fifteen years ago, we published that in Mexico, persons with CML were more frequently treated with hematopoietic stem cell transplantation (HSCT) than with TKIs due to the economic burden of long-term TKI administration7. Allogeneic HSCT (allo-HSCT) offers the possibility of long-term patient survival, so early consideration of transplantation is crucial based on the individual assessment of the risks and benefits of the potential patient8. In LMIC, including Mexico, allo-HSCT is usually preferred over TKIs since the one-time expense proper to transplantation is a superior cost-effective option to the life-long drug costs9.
Ten to 20 years ago, the most frequent indication of allo-HSCT throughout the world was CML10, but the development and approval of TKIs drastically changed the therapeutic scenario. After the first HSCT transplant at the Clínica Ruiz (Puebla, Pue., Mexico) in 199311, 1946 HSCTs have been performed as of August 2023; of these, 35 have been conducted in persons with CML. We herein analyze the long-term results of CML treatment with either an allo-HSCT or TKIs at the Clínica Ruiz and briefly discuss the current indications of these therapeutic approaches12.
MATERIALS AND METHODS
Patients
This research study was conducted retrospectively from data obtained for clinical purposes. All consecutive patients with CML diagnosed and treated at the Centro de Hematología y Medicina Interna de Puebla in Mexico, (CHMI) between 1994 and 2023 were included in the study. Peripheral blood (PB) smears stained with May-Grünwald Giemsa were reviewed and the diagnosis of CML was based on conventional criteria1. Cytogenetic markers were assessed and the presence of BCR-ABL1 fusion transcripts was detected by karyotyping, FISH, or multiplex RT-PCR13,14 after March 1999. Only Philadelphia chromosome (Ph1+) positive patients were included in the study.
All subjects provided written informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Centro de Hematolog.a y Medicina Interna, Clínica Ruiz.
Allografts
The reduced-intensity Mexican method to conduct allogeneic hematopoietic stem cell transplant was employed7. Briefly, we administered oral busulfan 4 mg/kg (days −4 and −5), intravenous (IV) cyclophosphamide (350 mg/m2 days −4, −3, −2 and −1), and IV fludarabine (25 mg/m2, days −4, −3 and −2) before the transplant. Preventive therapy of graft-versus-host disease (GVHD) included oral cyclosporine (100 mg every 8 h, day −1 until day +180), and IV methotrexate (5 mg/m2) on days +1, +3, +5, and +11. Oral cyclosporin A (CyA) was continued through day 180 with the necessary dose adjustments to maintain serum CyA levels between 150-275 ng/ml; it was subsequently tapered over 30-60 days. If GVHD signs or symptoms developed, CyA tapering continued for longer periods. Ondansetron (1 mg IV per hour, for 4 h after IV chemotherapy), oral cotrimoxazole, and an azole were administered to all patients; antibiotics and antimycotics were prescribed until the total granulocyte count increased above 500 granulocytes × 109/L. In all instances, the donor was an HLA-identical sibling. Products of the PBSC apheresis were reinfused on Day 0. Patients treated with allo-HSCT were patients who fulfilled the transplant criteria, including patients with no response to TKI treatment.
TKI treatment
All consecutive patients with Ph-positive and/or BCR-ABL1-positive CML in the chronic disease phase that were studied and treated in the Centro de Hematología y Medicina Interna de Puebla (CHMI, Puebla, Mexico) were included in the study. All patients were offered imatinib as initial therapy, beginning with a dose of 400 mg/day.
Follow-up
Patients were evaluated clinically every month after the begin of the treatment (TKI or allo-HSCT). The hematological response was evaluated with these criteria: complete hematological response (CHR) was defined as a white blood count of < 10 × 109/L, a platelet count of < 450 × 109/L, no immature cells (blasts, promyelocytes, and myelocytes) in the peripheral blood, and disappearance of all signs and symptoms related to leukemia (including palpable splenomegaly); partial hematological response (PHR) was defined as the presence of immature cells, platelet count < 50% of the pretreatment count but > 450 × 109/L, and persistent splenomegaly but < 50% of the pretreatment spleen size15.
For cytogenetic response, in our center, we evaluate the positivity or negativity of the Philadelphia (Ph) chromosome by a qualitative analysis, this analysis was repeated every 3 months for the 1st year and every 6 months afterward.
Statistics
The primary endpoint of the analysis was OS, defined as the interval from the start of treatment to death from any cause; it was estimated with Kaplan-Meier survival curves. Statistical analysis was performed with GraphPad Prism 9 (GraphPad Prism version 9 for Windows, GraphPad Software, San Diego, California USA, www.graphpad.com).
RESULTS
Patients
After 1994, 60 persons were diagnosed with Ph+ CML at the Centro de Hematología y Medicina Interna de Puebla; an allo-HSCT was conducted in 35 subjects, and after 2000, 25 received TKIs. All patients were in the chronic phase. HSCT with an HLA-identical sibling donor was offered to all CML patients; 35 had both a suitable donor and the capability of defraying the cost of the procedure. After 2000, patients who were not HSCT candidates were instructed to use TKIs. The median age was 38.5 (IQR: 27.7-49.2); there were 34 males and 26 females (Table 1). Twenty-one patients harbored the b2a2 transcript, 18 patients had b3a2, and 2 patients had the b2a2/b3a2 variant; the transcript could not be determined in the remaining.
Table 1 Salient features of the patients who received an allo-HSCT or were treated with a TKI
| Characteristics | TKI (n = 25) | allo-HSCT (n = 35) | p |
|---|---|---|---|
| Mean age | 38.84 ± 20.83 | 37.80 ± 12.86 | 0.812a |
| Female | 13 | 13 | 0.252b |
| Male | 12 | 22 | |
| Median survival (months) | Not reached | 78.33 (IC 95% 0-205.6) | 0.001c |
TKI: tyrosine kinase inhibitor; allo-HSCT: allogeneic hematopoietic stem cell transplantation.
ap value obtained with Student's t-test.
bp value obtained with the Chi-square test.
cp value obtained with the log-rank test.
Allografts
The years in which HSCTs were conducted are shown in Fig. 1. Clearly, most transplants were performed between 1999 and 2003. HSCT could be completed on an outpatient basis in 29/35 patients (83%). All patients engrafted successfully. The median time to recovery of > 0.5 × 109/L granulocytes was 16 days, whereas the median time to recover a platelet count above 20 × 109/L was 20 days. Acute GVHD developed in 12 patients (57%, Grades III/IV), and chronic GVHD developed in 9 (43%) patients. Eighteen (51%) patients have died, all between 11 and 216 months after the transplant. The causes of death are shown in table 2. Eleven of these patients were previously treated with a TKI before allo-HSCT: 6 patients received Imatinib, 4 received Dasatinib, and 1 received Nalotinib. After transplantation 26 patients were Ph negative, only one of these patients was positive again after 10 months. At the last evaluation, 10 patients showed a CHR, 25 PHR. The median follow-up was 14 months (IQR: 5.2-122.8 months), the number of patients lost to follow-up was 12, and deaths 17. Median OS was 78.3 months (CI 95%: 0-205.6) (Fig. 2).
Table 2 Causes of death in all the patients
| Cause of death | Number |
|---|---|
| GVHD | 12 |
| Uncontrolled leukemia | 3 |
| Graft failure | 1 |
| Hemorrhagic dengue | 1 |
| Car accident | 1 |
GVHD: graft versus host disease.
Patients treated with TKIs
Twenty-five patients with CML were offered TKIs after 2000: 21 were started on imatinib and 4 on dasatinib. Thirteen required switching to another TKI (3 with dasatinib and 10 with imatinib) due to gastrointestinal intolerance, headache, Sweet´s syndrome, or peripheral neuropathy (Table 3). Subsequently, 4 of 13 patients managed with a second TKI received a third TKI (2 imatinib, 1 ponatinib, and 1 nilotinib). Only one patient received a fourth TKI (nilotinib). After the start of treatment with TKI, 14 patients were Ph negative, two patients became positive again: one after 6 years and the other after 6 months. At the last evaluation, 20 patients showed a CHR, 5 PHR. The median follow-up was 34.6 months (IQR: 12.59-60.13 months), the number of patients lost to follow-up was 14, censored 10, and deaths 1. In the TKI cohort, the median OS was not reached, the Kaplan Meier OS curve is depicted in Fig. 2. The differences in OS between persons treated with TKIs or allo-HSCT are statistically different at the p = 0.001 level.
DISCUSSION
In high-income countries, TKIs are currently the first-line therapy of choice in persons with CML4. Imatinib is referred to as a first-generation TKI, dasatinib, nilotinib, bosutinib, and radotinib are second-generation, and ponatinib is a third-generation TKI16. The introduction of imatinib in 2001 as first-line therapy revolutionized the treatment of CML, transforming this disease from a fatal condition into a manageable chronic ailment. In LMIC, imatinib was initially priced at USD 30,000/patient/year, a cost that further increased over time, thus becoming an instantly inaccessible drug for most of the population around the globe, mainly in LMIC7. Nowadays the annual cost of therapy with generic imatinib in Mexico is around $4,500 dollars, however, the annual cost of dasatinib (second-generation TKI) is at least $55,000 dollars. As long as the costs of second-generation TKI´s remain significantly higher, imatinib will remain the choice as initial therapy. China, Mexico, Eastern Europe, and other Latin American countries favor allo-HSCT since this is a ‘once in a lifetime´ procedure and expense, in comparison with lifelong TKI therapy. In Mexico, the cost of an allo-HSCT is substantially lower than a 1-year treatment with the second or higher generation of TKIs13,14. The safety and effectiveness of allo-HSCT are continually improving and thus every health-care system must consider it an option in terms of cost-effectiveness when compared with TKI therapy4,5. When TKIs were introduced, the number of HSCT in patients with CML decreased substantially17; this occurred worldwide and was confirmed by our experience since the greatest number of persons with CML treated with an allo-HSCT in our center peaked between 1999 and 2003 (Fig. 1).
GVHD is an adverse immunological reaction mediated by donor T lymphocytes after allogeneic HSCT. Its incidence is 40-60% and its mortality rate is around 15%18. Depending on the time of presentation, this phenomenon is classified as acute (< 100 days post-HSCT) or chronic (> 100 days post-HSCT), and it is graded according to the extension of cutaneous manifestations and involvement of other systems and organs. GVHD significantly compromises the quality of life of persons who receive an allogeneic HSCT19. In the group of patients with CML whom we allografted, we found that although the graft prevented leukemic relapses, it compromised patient OS. GVHD was the most frequent cause of death in this subset of individuals (12/17, 70%).
The main adverse events that develop with TKI administration in patients with CML include abdominal pain, nausea, vomiting, diarrhea, anemia, neutropenia, thrombocytopenia, skin rash, fatigue, myalgia, arthralgia, headache, fluid retention, and among others; not all adverse events are associated with every TKI, and each drug tends to condition the development of drug-specific side effects9,20.
In our results, we observed that 11 patients did not present a favorable response to treatment with TKI, so these patients were treated with allo-HSCT. In young patients, the alternative to TKI treatment is HSCT, which is maintained as a one-time procedure and is a curative therapy. Since allo-HSCT has become less common in CML, its indications have changed over the past 10 years; it is currently an option if there is intolerance or resistance to TKIs, in a CML blast crisis, and if TKIs are either not available or not affordable to patients21,22. Interestingly, one of the indications of allo-HSCT in CML has not changed in the last 10 years: the obstacles imposed by the economic burden of the cost or lack of local availability of TKIs21,22, circumstances that encompass over 80% of the world´s population9.
As GVHD has become less aggressive and fatal due to preventive and therapeutic measures, the number of allogeneic HSCTs in persons with CML will likely improve, particularly in LMIC.
Fifteen years ago, we reported that over a 70-month observation period, the OS in patients with Ph1+ CML did not differ whether they were managed with TKIs or HSCT; however, cost-benefit analysis favored the use of HSCT. In this paper, by extending the period of observation to 280 months, we have demonstrated that OS is substantially superior among individuals who can afford treatment with TKIs (Fig. 1); however, allo-HSCT is still a valid therapeutic option in persons with CML living in LMIC, and who showed intolerance or resistance to TKIs or cannot afford treatment with TKIs23.
