Introduction

CML in its chronic phase starts as a rather benign phenotype, but its invariable transformation to the acute blast crisis gives the disease its true malignant character.^{1, 2} The ultimate goal of treatment for CML patients is to induce a molecular remission; cytogenetic remissions can be obtained with interferon or tyrosine kinase inhibitors (TKI), whereas molecular remissions can be achieved with TKIs or allogeneic SCT (allo-SCT). However, because SCT is limited to young patients with a suitable donor, it actually cures only about 15% of all patients with the disease.^{1, 2, 3} Although allo-SCT is a curative therapy for CML, treatment-related mortality is still a major cause of death after transplantation, especially in older patients. Nonablative stem cell transplantation (NST) has a lower transplant-related morbidity and mortality and induces a GVL effect that can eliminate all malignant cells by donor alloreactive immunocompetent cells. CML responds to the GVL effect;⁴ accordingly, we and others have used NST with success in patients with CML.^{4, 5, 6, 7}

The discovery and subsequent regulatory approval of imatinib and other TKIs has fundamentally changed the therapeutic algorithm for CML. Imatinib is now the therapy of choice for patients with newly diagnosed CML. This has had a profound impact on the use of allo-SCT for CML, with a marked decrease in the number of transplants for CML in developed countries.⁸ In developing countries, however, the impact has not been so marked,^{8, 9, 10} probably because of the cost of the TKIs. In México and probably in other developing countries, it is cheaper to perform an allo-SCT than to offer the patient a TKI.^{5, 6} In Eastern Europe, Latin America and probably other developing countries, cost considerations also favor allo-SCT as a 'once only' procedure in preference to lifelong treatment with an expensive drug which represents an excessive burden on resources.^{5, 6, 9, 10}

We report here the results of our multicenter experience in the treatment of CML, using either an allo-SCT employing the 'Mexican' non-ablative conditioning preparative regimen or treatment with TKI. Despite the fact that drug treatment is superior to allografting as first-line therapy in CML,¹¹ allografting still has a relevant role where resources are limited.

Materials and methods

Patients

All consecutive patients with Ph-positive and/or BCR–ABL-positive CML in a first chronic phase, studied and treated in the Centro de Hematología y Medicina Interna de Puebla (CHMI, Puebla, México) and in the Hospital Universitario de Nuevo León (HUNL, Monterrey, México) after January 1999, were prospectively recruited into the study; those treated with TKI were accrued after 2001, when imatinib became available in México. Table 1 shows some of the patient's salient features.

Table 1 - Salient features of the 72 patients with CML analyzed.

Full table

TKI treatment

Patients were given imatinib mesylate at an initial dose of 400 mg per day. The drug was either bought by the patients themselves or provided by the Glivec International Patient Assistance Program (GIPAP) system, administered by the Max Foundation (www.maxaid.org). Three patients were given dasatinib at a dose of 140 mg per day; this drug was donated by Bristol Myers Squibb México. All patients in one institution (HUNL) were given the TKIs free of charge and all patients in the other center (CHMI) paid for the TKIs themselves.

Allo-SCT

The 'Mexican method' of non-ablative conditioning preparative regimen was used in all patients given allo-SCT.^{5, 6} All the patients were in hematologic remission and had a Karnofsky's score of 100% when the procedure was performed. The donor was an HLA-identical (6 of 6) sibling in all instances. The protocol was approved by the institutional review board. Written consent was obtained from all the individuals. G-CSF (10 g/kg per day) was given to the sibling donors on day -5 to +2. One to three apheresis procedures were planned to be done on days 0, +1 and +2 by means of a Haemonetics V-50 PLUS machine (Haemonetics Corporation, Braintree, MA, USA), a Baxter C-3000 PLUS machine (Baxter Healthcare, Deerfield, IL, USA), an AMICUS (Baxter Healthcare) or a COBE Spectra (Gambro, Lakewood, CO, USA) using the Spin-Nebraska protocol.¹² The end point of collection was the processing of 5000–7000 ml of blood per m² in each of the three apheresis procedures, in order to obtain at least 5 10⁸ mononuclear (MNC) cells and/or 2 10⁶ viable CD34 cells per kg of the recipient's weight. The 'Mexican method' of nonablative conditioning was used.^{5, 6} Oral BU, 4 mg/kg was given on days -6 and -5; i.v. CY, 350 mg/m² on days -4, -3 and -2; i.v. fludarabine, 30 mg/m² on days -4, -3 and -2; oral CsA 5 mg/kg was started on day -1 and i.v. MTX 5 mg/m² was given on days +1, +3, +5 and +11. CsA was continued through day 180, with adjustments to obtain serum CsA levels of 150–275 ng/ml; it was then tapered over 30–60 days. If GVHD was present, the CsA was tapered over longer periods. Ondansetron (1 mg i.v. every hour during 4 h after i.v. chemotherapy), an oral quinolone and an azole were used in all patients following each center recommendation; antibiotics and antimycotics were used until granulocytes were >500 10⁶ per liter. The products of the PBSC apheresis were infused on days 0–2. Donor lymphocyte infusions were used 100 days after the allografts only if no evidence of GVHD was present and if there was evidence of persisting or relapsed leukemia. Enumeration of the total white blood, MNC and CD34–(+) cells was done by flow cytometry^{13, 14} in an EPICS Elite ESP apparatus (Coulter Electronics, Hialeah, FL, USA), using the anti-CD34 monoclonal antibody HPCA-2¹⁴ (Becton Dickinson, San José, CA, USA). No purging procedures were performed. Chimerism was assessed in cases with a sex mismatch with a fluorescent in situ hybridization technique to demonstrate the X and Y chromosomes;¹⁵ in cases with ABO system mismatch a flow cytometry-based approach was used, whereas polymorphic markers (short tandem repeats)¹⁶ were analyzed in the absence of the previously mentioned mismatches. BCR–ABL specific transcripts were detected by multiplex RT–PCR.¹⁷ The sensitivity for the detection of the BCR–ABL transcripts is about 10^-5 as determined previously by dilution experiments with K562 cells. The molecular studies were done at diagnosis, at 30 days after the allograft and every 3–6 months afterwards. Survival was calculated according to Kaplan and Meier.¹⁸

Results

Patients treated with TKI

A total of 50 consecutive patients able to get TKI were included; 47 received imatinib and 3 dasatinib. Forty-two patients (84%) were given the imatinib free through the GIPAP system; one patient received the imatinib manufactured in India and the remaining nine patients bought the imatinib by themselves. Imatinib was started at a dose of 400 mg per day in all patients and in 19 cases the dose was escalated to 500–800 mg per day. Median age of the patients was 39 years (range, 12–89). Median time from diagnosis to starting the TKI was 259 days (range, 0–2190). Forty-five patients are alive, 60–2130 days (median, 720) after starting the TKI. The projected 71-month overall survival (OS) is 84%; the median survival has not been reached, being above 2130 days (Figure 1). Five patients died 600–1080 (median, 840) days after starting the treatment, all as a result of progression of the disease. Forty-five patients had an initial hematological response; five failed to respond and two died. Eight patients developed progressive disease while being treated with imatinib (blast crisis in six cases). Thirty-eight patients achieved a major cytogenetic response and twenty-seven a molecular remission. The time to achieve a molecular remission ranged between 8 and 39 months (median, 20 months). Side effects of the treatment were cytopenias (15 patients), fluid retention (3 cases), arthralgias (2 cases) and dyspepsia (2 cases). Three patients received dasatinib after having received imatinib: one after developing a blast crisis while on imatinib, one after being unable to continue paying for the imatinib and one after developing a severe bone marrow hypoplasia while on imatinib. The freedom from progression to accelerated or blast phase in these patients was 79% at 71 months (Figure 2).

Figure 1.

Overall survival of patients with CML in first chronic phase either allografted (n=22) or given tyrosine-kinase inhibitors (TKI, n=50). The differences are not statistically significant using the log-rank ²-method. Survival curves begin at time of transplantation or at time of starting the treatment with TKIs.

Full figure and legend (9K)

Figure 2.

Freedom from progression to blast or accelerated phase of the patients with CML in first chronic phase either allografted or given tyrosine-kinase inhibitors (TKIs). The differences are not statistically significant using the log-rank ²-method. Curves begin at time of transplantation or at time of starting the treatment with TKIs.

Full figure and legend (9K)

Patients allografted

A total of 22 CML individuals in first CP were allografted; 21 of them (91%) chose this treatment because they were unable to afford the long-term treatment with a TKI. Twelve patients were female; median age was 38 years (range, 10–71). Median time from diagnosis to the allograft was 306 days (range, 46–1275). Since all patients were allografted in first chronic phase with cells from an HLA-identical sibling, all had low European Group for Blood and Marrow Transplantation risk scores, with a median of 1 (2 score 0, 10 score 1, 6 score 2 and 4 score 3). Patients received a median of 4.7 10⁶ per kg CD34(+) cells, using 1–3 (median, 2) apheresis procedures in the donors. Median time to achieve granulocytes >500 10⁶ per liter was 13 days, range 0–45, whereas median time to achieve platelets>20 10⁹ per liter was 12 days, range 0–54. Eighteen patients are alive, 30–2700 (median, 1020) days after the allograft. The projected 90-month OS is 77%, whereas median OS has not been reached, being above 2700 days. In total, 11 patients (50%) developed acute GVHD (9 grade I and 2 grade II) whereas 13 of 20 (65%) developed chronic GVHD (limited in 10 cases). In two instances, the chronic GVHD was fatal despite intensive immunosuppression and extracorporeal photopheresis. Four patients died 30–810 (median, 330) days after the allograft, two as the result of GVHD, one of sepsis and one as a result of progression of the disease. Eighteen patients achieved a molecular remission (undetectable BCR–ABL transcripts); all the patients who cleared the BCR–ABL transcripts were assessed for chimerism and found to be full chimeras. One patient never cleared BCR–ABL transcripts despite a cytogenetic response; she remains in a hematologic remission, with mixed chimerism 50 months after the allograft; she has been given donor lymphocyte infusions in three instances and has received imatinib and subsequently dasatinib. The BCR–ABL transcripts were cleared 16–190 days (median, 28) after the allograft. The transplant-related mortality was 13% (3 of 22); one patient experienced a relapse 27 months after the allograft was given imatinib and finally died. One patient died 30 days after the allograft as a result of sepsis with Pseudomonas aeruginosa. In 17 patients (77%) the whole procedure was completed on an outpatient basis. The freedom from progression to accelerated or blast phase in these patients was 80% at 90 months (Figure 2). Figure 3 depicts the OS of the patients after initial diagnosis.

Figure 3.

Overall survival for the patients with CML in first chronic phase either allografted (SCT=22) or given tyrosine-kinase inhibitors (TKI, n=50). The differences are not statistically significant using the log-rank ²-method. Survival curves begin at time of diagnosis.

Full figure and legend (9K)

Discussion

The standard options for treating patients with CML include allo-SCT, TKIs, hydroxyurea, interferon--based regimens and BU; however, the only curative treatment modality for these patients is allo-SCT.¹⁹ In the developed world, allo-SCT is now considered less frequently than before the TKI era;¹⁹ trials with imatinib, considered currently as the first-line therapy, have shown complete cytogenetic responses in over 80% of patients, with an OS over 90% and a freedom from progression to accelerated or blast phase in over 93% of patients.²⁰ There are emerging data about molecular remissions in patients on TKIs even after withdrawal.¹ TKIs have in addition an excellent safety profile and have fundamentally changed the treatment of CML patients in developed countries.

However, the scenario in underprivileged circumstances is clearly different. In developing countries, imatinib is available free of charge only to some individuals needing it. The median cost at a dose of 400 mg per day is US$ 100 per day. On the other hand, the median cost of the first 100 days of a nonmyeloablative allo-SCT in México is US$ 18 000,^{5, 6, 21, 22} whereas the median cost of a conventional allograft is US$ 30 000. It is evident that the early costs are lower with nonmyeloablative allo-SCT; however, the costs after the first 100 post-transplant days depend mainly on the development of GVHD and are not available in detail. As a result, in our country, with the money spent in the first 100 days of a nonmyeloablative allo-SCT, 180 days of continued treatment with imatinib can be afforded, provided the patient is given 400 mg per day of the drug.^{5, 6} In this scenario, most individuals in México and other developing countries choose to have an allo-SCT for economic reasons rather than other arguments to choose the treatment. Despite the fact that we do not have detailed data about the cost of giving allo-SCT to patients in other developing countries, the costs seem to be similar to those calculated for México, if nonablative preparative regimens are employed.⁶ In the young CML patient, other reasons for preferring a bone marrow allograft are uncertainty about the prolonged use of TKI's or the availability of the suitable donor, when identified. The data reported in this study suggest that the long-term results of using allo-SCT or TKI are not statistically different despite the fact that early mortality was observed in the allo-SCT group. It is also clear in this study that the rate of disappearance of the BCR–ABL transcripts was faster in allografted individuals (Table 1).

Allo-SCT has been shown to be useful in individuals with CML; reduced-intensity preparative regimens have been used successfully by us^{5, 6} and others^{4, 7, 23, 24, 25, 26, 27} and we have elected to use this preparative regimen for financial reasons.²⁸ Despite the fact that most studies with NST have a relatively short follow-up, there is information which indicates that the procedure has a similar long-term efficacy as that of conventional allografting.^{29, 30, 31} Since NST is more feasible and affordable for patients and physicians in developing countries,^{5, 6, 28, 29} the number of allografts in these places has increased substantially, as well as the publications related to bone marrow transplantation.²⁹

Allo-SCT as a consolidation treatment after inducing a remission in CML patients with a TKI seems to be a very useful option which combines the effectiveness of both treatment modalities and diminishes the need for lifelong treatment.¹

Despite the fact that drug treatment is superior to allografting as first-line therapy in CML in developed countries,¹¹ allografting has still a role where resources are limited. For over 50% of the inhabitants of the world, financial considerations may favor allo-SCT as a one-in-a-lifetime procedure instead of lifelong treatment with an expensive drug which would represent an excessive burden on resources. While the initial cost of allo-SCT may be higher both to the society and the individual, it may still have a better lifetime economic value.^{32, 33} Longer follow-up is necessary to confirm these observations.

References

1. Goldman JM. Advances in CML. Clin Adv Hematol Oncol 2007; 5: 270–272. | PubMed |
2. Gómez-Almaguer D. Leucemias crónicas. In: Ruiz-Argüelles GJ (ed). Fundamentos de Hematología, 3rd edn. Editorial Médica Panamericana: México City, 2004, pp 246–260.
3. Ruiz-Argüelles GJ, López-Martínez B, Ramírez-Cabrera JM, Reyes-Nuñez V, Rodríguez-Cedeño H, Garcés-Eisele J. Molecular monitoring of the treatment of patients with BCR/ABL(+) chronic myelogenous leukemia. Rev Invest Clín Méx 2001; 53: 235–239.
4. Or R, Shapira MY, Resnick I, Amar A, Ackerstein A, Samuel S et al. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood 2003; 101: 441–445. | Article | PubMed | ISI | ChemPort |
5. Ruiz-Argüelles GJ, Gómez-Almaguer D, López-Martínez B, Cantú-Rodríguez OG, Jaime-Pérez JC, González-Llano O. Results of an allogeneic non-myeloablative stem cell transplantation program in patients with chronic myelogenous leukemia. Haematologica 2002; 87: 894–896. | PubMed |
6. Ruiz-Argüelles GJ, Gómez-Almaguer D, Morales-Toquero A, Gutiérrez-Aguirre CH, Vela-Ojeda J, García-Ruiz-Esparza MA, et al., Latin American Cooperative Oncohematology Group. The early referral for reduced-intensity stem cell transplantation in patients with Ph1 (+) chronic myelogenous leukemia in chronic phase in the imatinib era: results of the Latin American Cooperative Oncohematology Group (LACOHG) prospective, multicenter study. Bone Marrow Transplant 2005; 36: 1043–1047. | Article | PubMed | ISI | ChemPort |
7. Okamoto S, Watanabe R, Takahashi S, Mori T, Izeki T, Nagayama H et al. Long-term follow-up of allogeneic bone marrow transplantation after reduced-intensity conditioning in patients with chronic myelogenous leukemia in the chronic phase. Int J Hematol 2002; 75: 493–498. | PubMed | ISI | ChemPort |
8. Giralt SA, Arora M, Goldman JM, Lee SJ, Maziarz RT, McCarthy PL et al. Impact of imatinib therapy on the use of allogeneic haematopoietic progenitor cell transplantation for the treatment of chronic myeloid leukaemia. Br J Haematol 2007; 137: 461–467. | Article | PubMed | ChemPort |
9. Gratwohl A, Brand R, Apperley J, Crawley C, Ruutu T, Corradini P et al. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation: allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 2006; 91: 513–521. | PubMed | ISI |
10. Gratwohl A, Baldomero H, Labar B, Apperley J, Urbano-Ispizua A, Accreditation Committee of the European Group for Blood and Marrow Transplantation (EBMT). Evolution of hematopoietic stem cell transplantation in Eastern and Western Europe from 1990 to 2003. A report from the EBMT activity survey. Croat Med J 2004; 45: 689–694. | PubMed |
11. Hehlmann R, Berger U, Pfirrmann M, Heimpel H, Hochhaus A, Hasford J et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 2007; 109: 4686–4692. | Article | PubMed | ISI | ChemPort |
12. Kessinger A, Armitage JO, Landmark JD, Smith DM, Weisenburger DD. Autologous peripheral hematopoietic stem cell transplantation restores hematopoietic function following marrow ablative therapy. Blood 1998; 71: 723–727.
13. Ruiz-Argüelles A. Flow cytometry in the clinical laboratory. Principles, applications and problems. Ann Biol Clin 1992; 50: 735–743.
14. Ruiz-Argüelles A, Orfao A. Caracterización y evaluación de células totipotenciales en sangre periférica y médula ósea. In: Ruiz-Argüelles GJ, San-Miguel JF (eds). Actualización en Leucemias. Editorial Médica Panamericana: México City, 1996, pp 79–82.
15. Pinkel D, Straume T, Gray JW. Cytogenetic analysis using quantitative, high sensitivity fluorescence hybridization. Proc Natl Acad Sci USA 1996; 83: 2934–2938. | Article |
16. Yam P, Petz L, Knowlton R, Wallace R, Stock A, deLange G et al. Use of DNA restriction fragment length polymorphisms to document marrow engraftment and mixed hematopoietic chimerism following bone marrow transplantation. Transplantation 1987; 43: 399–407. | Article | PubMed | ISI | ChemPort |
17. Ruiz-Argüelles GJ, Garcés-Eisele J, Reyes-Núñez V, Pérez-Romano B, Ruiz-Argüelles A, Ramírez-Cisneros F et al. Assessment of residual disease in acute leukemia by means of polymerase chain reaction: a prospective study in a single institution. Rev Invest Clin Mex 2000; 52: 118–124.
18. Kaplan EL, Meier P. Nonparametric estimations from incomplete observations. J Am Stat Assoc 1958; 53: 457–463. | Article | ISI |
19. Hehlmann R, Hochhaus A, Baccarani M. European Leukemia Net: chronic myeloid leukaemia. Lancet 2007; 370: 342–350. | Article | PubMed | ChemPort |
20. Druker BJ, Guilhot F, O'Brien SO, Larson RA, on behalf of the IRIS. Long-term benefits of imatinib for patients newly diagnosed with chronic myelogenous leukemia in chronic phase: the 5-year update from the IRIS study. J Clin Oncol 2006; 24 (suppl): 6506.
21. Gómez-Almaguer D, Ruiz-Argüelles GJ, Ruiz-Argüelles A, González-Llano O, Cantú OE, Hernández NE. Hematopoietic stem cell allografts using a non-myeloablative conditioning regimen can be safely performed on an outpatient basis. Bone Marrow Transplant 2000; 25: 131–133. | Article | PubMed |
22. Ruiz-Argüelles GJ, Gómez-Almaguer D, Ruiz-Argüelles A, González-Llano O, Cantú OG, Jaime-Pérez JC. Results of an outpatient-based stem cell allotransplant program using non-myeloablative conditioning regimens. Am J Hematol 2001; 66: 241–244. | Article | PubMed | ISI | ChemPort |
23. Weisser M, Schleuning M, Ledderose G, Rolf B, Schnittger S, Schoch C et al. Reduced-intensity conditioning using TBI (8 Gy), fludarabine, cyclophosphamide and ATG in elderly CML patients provides excellent results especially when performed in the early course of the disease. Bone Marrow Transplant 2004; 34: 1083–1088. | Article | PubMed | ISI | ChemPort |
24. Basara N, Roemer E, Kraut L, Guenzelmann S, Schmetzer B, Kiehl MG et al. Reduced intensity preparative regimens for allogeneic hematopoietic stem cell transplantation: a single center experience. Bone Marrow Transplant 2002; 30: 651–659. | Article | PubMed | ISI | ChemPort |
25. Khoury H, Adkins D, Brown R, Pence H, Vij R, Goodnough LT et al. Low incidence of transplantation related acute complications in patients with chronic myeloid leukemia undergoing allogeneic stem cell transplantation with a low-dose (550 cGy) total body irradiation conditioning regimen. Biol Blood Marrow Transplant 2001; 7: 352–358. | Article | PubMed | ISI | ChemPort |
26. Das M, Saikia TK, Advani SH, Parikh PM, Tawde S. Use of a reduced-intensity conditioning regimen for allogeneic transplantation in patients with chronic myeloid leukemia. Bone Marrow Transplant 2003; 32: 125–129. | Article | PubMed | ISI | ChemPort |
27. Baron F, Maris MB, Storer BE, Sandmaier BM, Stuart MJ, McSweeney PA et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with chronic myeloid leukemia. Biol Blood Marrow Transplant 2005; 11: 272–279. | Article | PubMed | ISI |
28. Gómez-Almaguer D. The simplification of the stem cell procedures in developing countries has resulted in cost-lowering and availability to more patients. Int J Hematol 2002; 76 (Suppl 1): 380–382. | PubMed | ISI |
29. Ruiz-Argüelles GJ, Gómez-Almaguer D, Ruiz-Delgado GJ, Tarín-Arzaga LC. Ocho años de experiencia con el 'método Mexicano' en la realización de trasplantes de células hematopoyéticas alogénicas. Gac Med Mex 2007; 143: 231–235. | PubMed |
30. Couriel DR, Saliba RM, Giralt S, Khouri I, Andersson B, de Lima M et al. Acute and chronic graft versus-host-disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 2004; 10: 178–185. | Article | PubMed | ISI |
31. Battiwalla M, Barrett J. Allogeneic transplantation using non-myeloablative transplant regimens. Best Pract Res Clin Haematol 2001; 14: 701–722. | Article | PubMed | ChemPort |
32. Gratwohl A, Baldomero H, Schwendener A, Gratwohl M, Urbano-Ispizua A, Frauendorfer K. Hematopoietic stem cell transplants for chronic myeloid leukemia in Europe. Impact of cost considerations. Leukemia 2007; 21: 383–386. | Article | PubMed | ISI | ChemPort |
33. Gajewski JL, Robinson P. Do affluent societies have the only option for the best therapy? Leukemia 2007; 21: 387–388. | Article | PubMed | ISI | ChemPort |