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Year : 2003  |  Volume : 40  |  Issue : 4  |  Page : 140-143

Early relapse after non myeloablative allogeneic stem cell transplantation in a patient with acute promyelocytic leukemia in complete molecular remission

Service d'Hematologie Clinique, Hopital Edouard Herriot, 69437 Lyon cedex 03, France

Correspondence Address:
Xavier Thomas
Service d'Hematologie Clinique, Hopital Edouard Herriot, 69437 Lyon cedex 03
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Source of Support: None, Conflict of Interest: None

PMID: 14716110

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 » Abstract 

We described a 41-year-old patient with acute promyelocytic leukemia (APL) who experienced two successive relapses: one after all-trans retinoic acid (ATRA) treatment and chemotherapy, and another after ATRA treatment and chemotherapy, followed by autologous peripheral blood stem cell transplantation. A third complete remission (CR) was achieved with arsenic trioxide (As2O3) therapy. Mini-transplantation was performed as consolidation therapy. While the patient was in molecular remission at the beginning of conditioning regimen, a new relapse arose after transplantation at time of cell recovery. This raises a potential relationship between relapse and the severe immunosuppression induced by mini-transplantation. To our knowledge, this is the first description of a mini-allograft in an APL patient achieving molecular remission after As2O3 therapy.

Keywords: Acute promyelocytic leukemia, Mini-transplantation, Relapse

How to cite this article:
Tavernier E, Thomas X. Early relapse after non myeloablative allogeneic stem cell transplantation in a patient with acute promyelocytic leukemia in complete molecular remission. Indian J Cancer 2003;40:140-3

How to cite this URL:
Tavernier E, Thomas X. Early relapse after non myeloablative allogeneic stem cell transplantation in a patient with acute promyelocytic leukemia in complete molecular remission. Indian J Cancer [serial online] 2003 [cited 2020 Jul 15];40:140-3. Available from:

 » Introduction Top

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) corresponding to the first example of therapy targeted to a specific genetic marker.[1] The combination of all-trans retinoic acid (ATRA) with anthracycline-based chemotherapy has significantly improved the complete remission (CR) rate and transformed the outcome of newly diagnosed APL.[2] However, relapses still occur in 20 to 30% of cases. At that time, different strategies, of which intensive chemotherapy combined or not with ATRA followed either by autologous stem cell transplantation (SCT)[3] or allogeneic bone marrow transplantation (BMT),[4] have been proposed. More recently, studies have shown arsenic trioxide (As2O3), eventually followed by SCT, to be a highly effective therapy for patients with relapsed APL.[5] Concomitantly, mini- or micro-transplantations have shown promising results and have been developed[6] to reduce the toxicity of conditioning regimens and to preserve a curative antileukemic effect corresponding to allogeneic SCT after a non myeloablative preparative regimen, whether followed by donor lymphocyte infusions (DLI) or not, according to both chimerism and results of minimal residual disease documentation.

In this report, we describe an 41-year-old man who presented with an atypical outcome of APL characterized by successive relapses, of which one occurred early after undergoing mini-transplantation as consolidation therapy while in molecular remission.

 » Case report Top

A 41-year-old Moroccan man without any prior personal medical history (except a medicinal hepatitis in his youth) was first admitted to hospital with complaints of prolonged bleeding after teeth extractions in June 1997. Biological tests showed coagulation disorders with low fibrinogen levels and presence of fibrin degradation products. Peripheral blood showed severe thrombocytopenia (16 x 109/l) combined with leukopenia (1.2 x 109/l) (12% blasts). Bone marrow aspirates showed typical findings of APL with hypergranular blasts, many with multiple  Auer rods More Details.[7] Diagnosis of APL was confirmed by cytogenetic analysis showing metaphases with the t(15;17) translocation. Molecular biology showed PML/RARa rearrangement. Treatment was administered according to APL 93 chemotherapy protocol[8] including one induction course, followed by two consolidation courses and a maintenance therapy over two years. The induction course consisted of daunorubicin (60 mg/m2/day) for 3 days and cytarabine (200 mg/m2/day) for 7 days, combined with oral ATRA (45 mg/m2/day) from day 1 to CR achievement. Aplasia following the course of chemotherapy was marked by staphylococcus septicemia and thrombophlebitis requiring a surgical cure. Complete remission was achieved by day 28. First consolidation chemotherapy was similar to induction chemotherapy (without ATRA). Second consolidation included daunorubicin (45 mg/m2/day) for 3 days and cytarabine (1 g x 2/m2/day) for 4 days. Ambulatory maintenance therapy comprised continuous 6-mercaptopurine plus methotrexate. Treatment was well tolerated. Unfortunately, relapse occurred in October 1999 after 20 months of maintenance therapy. The patient was retreated according to a schedule combining oral ATRA (45 mg/m2/day) from day 1 to CR achievement, followed by EMA-timed sequential chemotherapy combining etoposide (200 mg/m2/day) for 3 days, mitoxantrone (12 mg/m2/day) for 3 days, and cytarabine (500 mg/m2/day) for 2 sequences of 3 days.[3] After second CR achievement, stem cell were mobilized in stable phase by granulocyte colony-stimulating factor (G-CSF) given at the dose of 5 µg/kg/day for 5 days. Only one cytapheresis was required yielding to harvest 6.02 x 106 CD34+ cells/kg. Autologous peripheral SCT was performed in February 2000. Myeloablative conditioning regimen consisted of cyclophosphamide (60 mg/kg/day) for two days followed by fractionated total body irradiation (TBI) (12 Gy). A second relapse occurred 5 months later in July 2000. The patient was enrolled into a phase I/II clinical trial studying the efficacy of arsenic trioxide (As2O3) in relapsed acute promyelocytic leukemia patients.[9] He received As2O3 (0.2 mg/kg/day) combined with ATRA (45 mg/m2/day) for 28 days. Side effects involving fever, edema, pericardiac and pleural effusions, and hyperleukocytosis (white blood cell count > 100 x 109/l) were observed on day 24. They were quickly relieved by steroids and amsacrine (150 mg/day) administration for 3 days. A third CR was achieved with both morphologic, cytogenetic and molecular (< 10-6) criteria. This first course was followed by 2 consolidation courses with As2O3 and ATRA for 28 days. Allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling was theoretically regarded as the best consolidation therapy that could be proposed to prevent relapse. However, conventional allogeneic BMT was not considered because of high-dose therapy previously received and of severe side-effects potentiation. Non myeloablative conditioning regimen was preferred, based on 2 Gy TBI on day-1 followed by immunosuppression combining cyclosporine (3 mg/kg/day) from day -3 to day 56 and the novel immunosuppressive mycophenolate mofetil (15 mg/kg/day) from day 0 to day 27.[10] The donor was patient's 33-year-old young brother. Allogeneic transplant was performed in February 2001 from donor's harvested hematopoietic peripheral stem cells mobilized by G-CSF. Hospitalization went off without any complications. A new relapse was suspected at time of cell recovery on the reappearance of circulating blasts and signs of coagulopathy. Relapse was confirmed by bone marrow aspirates and karyotypic analysis. A mixed-chimerism was observed in bone marrow with 40% of cells from recipient. Salvage chemotherapy, combining ATRA (45 mg/m2/day) with idarubicin (12 mg/m2/day) for 3 days and cytarabine (1 g/m2/12 hours) for 5 days,[11] followed at day 13 by donor lymphocyte infusion (DLI) (1 x 108 CD3 cells/kg of recipient body weight) did not permit to achieve a new CR. The patient finally died in progressive disease in May 2001 from pulmonary invasive aspergillosis.

 » Discussion Top

This case raises different interesting points. First of all, it points to the possibility of masked ATRA resistance in some APL patients in whom ATRA was given concomitantly to chemotherapy. Complete remission can be achieved with ATRA in most APL patients through in vivo differentiation of leukemic blasts. Overall more than 90% of patients with newly diagnosed APL can achieved complete remission, and about 75% can be cured by the combination of ATRA and chemotherapy. A risk-adapted strategy combined anthracycline monochemotherapy and ATRA is now being applied to newly diagnosed APL resulting in improved antileukemic efficacy and a high degree of compliance.[12] Indeed, increasing the doses of anthracyclines during consolidation could lower the relapse rate in the high-risk group of patients. Resistance to ATRA was generally seen in fewer than 2% of the patients if diagnosis is confirmed. This situation is unusual in cytogenetically [t(15;17)] or molecularly (PML-RARa rearrangement) confirmed APL. Chemotherapy possibly overcame partial resistance to ATRA. In our case report, there was an apparent response to ATRA therapy. But, ATRA was always used concomitantly to chemotherapy and the outcome was closer to that generally observed in non promyelocytic AML. Relapses occurred after shorter and shorter complete remission durations confirming the development of drug resistance. This reinforce the critical importance of the differentiating therapy of APL and suggest that enhancement in treatment efficacy should involve enhancement of the differentiation step, which could be possible by association of synergistic differentiating agents. The sensitivity of leukemic clone to ATRA at diagnosis is a determinant of long-term patient outcome.[13] Expression of resistance at the time of diagnosis is associated with substantially worse outcome. There are several obvious regions where retinoid resistance might arise. Such resistance must necessarily be related rather than absolute. Indeed, it is difficult to envision a complete insensitivity to an essential regulatory molecule that normally functions in so many critical pathways. It does not appear that clinically induced resistance is permanent. Pharmacologic alterations in the metabolism of ATRA are responsible for clinical retinoid resistance. Some individuals achieve very low plasma drug levels even with their first dose. Differences in catabolic rates occur without prior exposure to exogenous retinoids. There may well be both genetic and environmental explanations for such metabolic differences. After relapse, ATRA can be an effective therapy used again to achieve a CR in 70-80% of cases but resistance to ATRA usually develops inexorably. This can be explained by lower plasma drug concentrations due to an induced hypercatabolism and by increased expression of cytoplasmic retinoic acid binding protein (CRABP).[14] Generally, patients who relapse while taking ATRA cannot achieve remission again by further treatment with ATRA, although there seems to be no increase in resistance to conventional chemotherapy. Relapses occurring shortly after discontinuation of ATRA are usually resistant to ATRA, even at higher doses. Later relapses may respond to ATRA.[2]

Secondly, our observation points to the confirmed efficacy of arsenic trioxide in relapsing APL.[15] In clinical trials, CR can be achieved in 85% of patients.[16] Arsenic compounds can be a very interesting option in case of resistance to ATRA and chemotherapy. The main cellular mechanisms of As2O3 seem to be the degradation of PML-RARa oncoprotein and mainly the induction of apoptosis of APL cells. At lower doses, it also exerts a differentiating effect. Combinations of different agents surely represent a fruitful area for the purpose of overcoming resistance. As2O3 and ATRA target the PML-RARa fusion protein and cause remission in APL through distinct mechanisms of action, suggesting the possibility of synergistic effects between the two drugs. Similarly, it has been shown better results with As2O3/chemotherapy combination than with As2O3 alone. As2O3 can lead to molecular remission at the time of CR in the majority of patients.[5],[17] This was the case for our patient since a molecular remission was observed after As2O3/ATRA combination therapy. However, the details of how best to use arsenic trioxide to achieve optimal efficacy are unknown at this time. Although still preliminary, data suggest that patients in first or subsequent relapse following ATRA/anthracycline therapy will benefit when they are treated with arsenic trioxide before transplantation. They seem to indicate that arsenic trioxide does not produce toxicities seen with regimens involving aggressive chemotherapy. As2O3 thus appears to reduce the risk of transplantation-related complications.

Finally, our case report questions about the opportunity to perform non myeloablative allogeneic transplant in highly immunocompromized patients. Because of the overall favorable outcome of APL, BMT procedures does not represent the treatment of choice in first CR. Autologous or allogeneic SCT are routinely employed as post-consolidation therapy for patients with APL in second CR. The relatively good outcome and low transplantation-related mortality are features that support the use of autologous SCT, especially in the absence of minimal residual disease, in patients in second or further CR.[3] However, autologous stem cell transplantation did not prevent our patient from a second relapse. Mini-transplantation has recently been developed to reduce the toxicity of conditioning regimens and to preserve a curative antileukemic effect corresponding to allogeneic hematopoietic SCT after a non myeloablative preparative regimen, whether followed by DLI or not, according to both chimerism and results of minimal residual disease documentation.[10] Our case report represent the first description of a mini-allograft for an APL patient achieving molecular remission with As2O3 therapy. Mini-transplantation represented theoretically the treatment of choice as consolidation. Indeed, myeloablative allogeneic BMT, that could not be performed in second CR for practical reasons (donor living abroad), has been rejected in third CR because of its potential toxicity. A low-intensity regimen has been preferred in this over-treated patient and the potential use of DLI has been considered after transplant. However, our patient relapsed a short time after mini-transplantation. Could the immuno-suppression induced for the mini-allograft combined with that resulting from previous intensive therapies be the reason for relapse? High-dose cyclosporine A has previously been associated with an increased incidence of relapse.[18] We can therefore hypothesized that the successive immunosuppressive therapies could have favored the reemergence of the leukemic clone despite undetectable minimal residual disease before transplant as confirmed by negative PCR results. Reemergence of the leukemic clone seemed associated with total resistance to further chemotherapy and to adoptive immunotherapy using DLI. This calls for caution in the indications of mini-transplantation. Large series are warranted to better assess such a procedure.

 » References Top

1.Parmar S, Tallman MS. Acute promyelocytic leukaemia: a review. Expert Opin Pharmacother 2003;4:1379-92.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. Blood 1993;82:3241-9.  Back to cited text no. 2    
3.Thomas X, Dombret H, Cordonnier C, Pigneux A, Gardin C, Guerci A, et al. Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. Leukemia 2000;14:1006-13.  Back to cited text no. 3    
4.Mandelli F, Labopin M, Granena A, Iriondo A, Prentice G, Bacigalupo A, et al. European survey of bone marrow transplantation in acute promyelocytic leukaemia (M3). Bone Marrow Transplant 1994;14:293-8.  Back to cited text no. 4  [PUBMED]  
5.Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852-60.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Carella AM, Champlin R, Slavin S, McSweeney P, Storb R. Mini-allografts: ongoing trials in humans. Bone Marrow Transplant 2000;25:345-50.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) Co-operative Group. Br J Haematol 1976;33:451-62.  Back to cited text no. 7    
8.Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. Blood 1999;94:1192-200.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Raffoux E, Rousselot P, Poupon J, Daniel MT, Cassinat B, Delarue R, et al. Combined treatment with arsenic trioxyde and all-trans retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 2003; 21:2326-34.  Back to cited text no. 9    
10.Maris M, Storb R. The transplantation of hematopoietic stem cells after non-myeloablative conditioning: a cellular therapeutic approach to hematologic and genetic diseases. Immunol Res 2003;28:13-24.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Belhabri A, Thomas X, Wattel E, Chelghoum Y, Anglaret B, Vekhoff A, et al. All-trans retinoic acid in combination with intermediate-dose cytarabine and idarubicin in patients with relapsed or refractory non promyelocytic acute myeloid leukemia: a phase II randomized trial. The Hematology Journal 2002;3:49-55.  Back to cited text no. 11  [PUBMED]  
12.Sanz MA, Martin G, Gonzalez M, Leon A, Rayon C, Rivas C, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEM Group. Blood 2003; [Epub ahead of print].  Back to cited text no. 12    
13.Agadir A, Cornic M, Lefebvre P, Gourmel B, Jerome M, Degos L, et al. All-trans retinoic acid pharmacokinetics and bioavailability in acute promyelocytic leukemia: intracellular concentrations and biological response relationship. J Clin Oncol 1995;13:2517-23.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Delva L, Cornic M, Balitrand N, Guidez F, Miclea JM, Delmer A, et al. Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukaemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells. Blood 1993; 82:1949-53.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Liu P, Han ZC. Treatment of acute promyelocytic leukemia and other hematologic malignancies with arsenic trioxide: review of clinical and basic studies. Int J Hematol 2003;78:32-9.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Niu C, Yan H, Yu T, Sun HP, Liu XS, Li XS, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999;94:3315-24.  Back to cited text no. 16    
17.Lazo G, Kantarjian H, Estey E, Thomas D, O'Brien S, Cortes J. Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the M.D. Anderson experience. Cancer 2003;97:2218-24.  Back to cited text no. 17    
18.Bacigalupo A, van Lint MT, Occhini D, Gualandi F, Lamparelli T, Sogno G, et al. Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Blood 1991;77:1423-8.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]


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