Allogeneic bone marrow transplantation improves the ... - Nature

Leukemia (2000) 14, 1861–1866  2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu

Allogeneic bone marrow transplantation improves the outcome of de novo AML with trilineage dysplasia (AML-TLD) J Taguchi1, Y Miyazaki1, S Yoshida1, T Fukushima1, Y Moriuchi2, I Jinnai1, T Matsuo3, K Kuriyama1 and M Tomonaga1 1 Department of Hematology and Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Nagasaki; 2Sasebo City General Hospital, Sasebo; and 3Blood Transfusion Service, Nagasaki University Hospital, Nagasaki, Japan

De novo acute myeloid leukemia (AML) with dysplastic features in erythroblasts, granulocytes and megakaryocytes, similar to those in myelodysplastic syndrome (MDS) has been described as AML with trilineage dysplasia (AML-TLD) since 1987. Several reports have suggested that AML-TLD is a subtype of de novo AML in adults and has a poor clinical outcome when treated by conventional chemotherapy. It is not certain whether allogeneic bone marrow transplantation (BMT) brings a favorable outcome for AML-TLD. To evaluate the therapeutic efficacy of allogeneic BMT for AML-TLD, we investigated the clinical data and outcomes of conventional chemotherapy and allogeneic BMT for 118 patients with de novo AML. These patients were registered consecutively for the Japan Adult Leukemia Study Group (JALSG) protocols at our institutes. We treated 28 AML-TLD patients and 90 AML-nonTLD patients with conventional chemotherapeutic protocols. AML-TLD patients did not have a significantly different complete remission (CR) rate (75.0% and 88.4% P = 0.1234), but had a significantly higher relapse rate than AML-nonTLD patients (94.1% and 49.3%, P = 0.0007). The outcome of chemotherapy for AML-TLD was significantly worse than that for AML-nonTLD. The overall survival (OS) and leukemia-free survival (LFS) at 6 years were 9.4% and 0% in AMLTLD group, and 51.9% (P = 0.0017) and 46.3% (P ⬍ 0.0001) in AML-nonTLD group, respectively. Meanwhile, among the patients who underwent allogeneic BMT, five of eight AML-TLD patients and eight of 14 AML-nonTLD patients were alive, and three and five patients survived more than 3 years, respectively. These results suggest that allogeneic BMT can improve the outcome for AML-TLD, which is poor when conventional chemotherapy is given alone. Allogeneic BMT before relapse may be the best therapeutic strategy for AML-TLD patients under 50 years of age if a donor is available. Leukemia (2000) 14, 1861–1866. Keywords: AML; trilineage dysplasia; chemotherapy; allogeneic bone marrow transplantation

Introduction The outcome of treatment for adults with AML has improved substantially during the past 20 years. However, long-term survival occurs in only 25–45% of patients who achieve complete remission (CR). Myeloablative treatment with allogeneic BMT has become an option of treatment for AML patients younger than 50 years, but allogeneic BMT does not generally seem to improve survival; it may provide a better outcome than chemotherapy in a portion of AML patients. Thus, it is clinically important to know which patients benefit from allogeneic BMT. AML-TLD was first reported as a subtype of de novo AML in 1987, showing morphological dysplasia of mature hematopoietic cells against a background of leukemic blasts.1,2

Correspondence: J Taguchi, Department of Hematology and Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Sakamoto 1-12-4, Nagasaki, 852-8523, Japan; Fax: 81 95 849 7113 Received 24 February 2000; accepted 18 July 2000

Although the dysplastic features seen in AML-TLD are similar to those in MDS, the absence of preceding hematological abnormality distinguishes AML-TLD from leukemias following MDS. The outcome of intensive chemotherapy for AML-TLD is usually worse in terms of the CR rate and survival than for AML-nonTLD.1–5 We previously reported two AML-TLD patients treated with allogeneic BMT,6 but the efficacy of allogeneic BMT for AML-TLD has not been evaluated. In the present study, to clarify the efficacy of allogeneic BMT for AML-TLD, we analyzed the clinical data and outcomes of 118 patients with de novo AML registered consecutively for the Japan Adult Leukemia Study Group (JALSG) protocols at our institutes. Twenty-eight of 118 patients were classified as AML-TLD (treated with chemotherapy) and eight out of these 28 (AML-TLD) patients underwent allogeneic BMT. We report here that allogeneic BMT provides a favorable outcome for AML-TLD and propose that it be considered in patients during first CR. Patients and methods

Patients From July 1987 to November 1997, 119 newly diagnosed adult patients with de novo AML were registered consecutively for the JALSG at our institutes. One patient was excluded from the analyses due to lack of data, and 28 patients were classified as AML-TLD. Patients who had a preceding hematological abnormality such as MDS or myeloproliferative disorders and with a history of exposure to chemotherapy or radiation therapy were excluded. Finally, we analyzed the clinical characteristics and outcomes of 118 patients. Patients with acute promyelocytic leukemia (FABM3) were excluded from the analyses after 1992, because they were treated with different protocols using all-trans retinoic acid (ATRA). Eight of 28 AML-TLD and 14 of 90 AML-nonTLD patients underwent allogeneic BMT during the period of this study.

Chemotherapy Patients were treated according to the JALSG protocols. There were four protocols (AML87, AML89, AML92 and AML95) and 19, 28, 44 and 27 patients were treated with each, respectively. The first three protocols, which have been described in detail before,7–9 had similar therapeutic regimens. The remission induction regimen consisted of daunorubicin (DNR; 40–50 mg/m2 for 3 days) and cytosine arabinoside (Ara-C; 100 mg/m2 for 7–10 days) or behenoyl cytarabine (BHAC; 200 mg/m2 for 7–10 days) mainly. The AML95 protocol had a remission induction therapy including

Allogeneic BMT improves the outcome of AML-TLD J Taguchi et al

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idarubicin (IDA; 12 mg/m2 for 3 days) and Ara-C (100 mg/m2 for 7 days). After achieving CR, patients received three courses of consolidation therapy, followed by 6–12 courses of maintenance therapy. The consolidations mainly consisted of BHAC or Ara-C combined with one of three drugs (DNR, mitoxantrone or aclarubicin).

Allogeneic BMT The conditioning regimens were divided into two categories; one was the combination of busulfan (BU) + cyclophosphamide (CY) and the other was total body irradiation (TBI)-based regimens. These regimens were performed following the standard methods:10,11 the dose of BU was 16 mg/kg, that of CY was 120–180 mg/kg and that of TBI was 12 Gy. Methotrexate (MTX) and cyclosporin (CsA) or tacrolimus (FK506) were administered for the prophylaxis of GVHD.12 The combination of CsA and short-term MTX, and FK506 and short-term MTX was administered mainly for patients with an HLAmatched donor source, and with HLA-mismatched or unrelated donor source, respectively. Acute GVHD was graded according to standard criteria.13 None of the patients received T cell-depleted marrow. Allogeneic BMT was performed in a room with laminar air-flow. Patients were given low bacteria diets, gut decontamination with absorbable antibiotics and antifungal medications. Trimethoprim-sulfamethoxazole and gamma globulin were administered for the prophylaxis of Pneumocystis carinii and cytomegaloviral interstitial pneumonia, respectively. Six patients who received transplantation during first remission were thought to be at risk for early relapse of leukemia; three patients showed TLD features (one of them had complex chromosomal abnormality), two had high WBC count at diagnosis and one needed three courses of induction therapy to achieve CR.

junction with other abnormalities. The intermediate risk group included patients with a normal karyotype and the other abnormalities not classified as favorable or adverse. The adverse risk group included patients with a complex karyotype with three or more numerical or structural aberrations, −5, deletion (5q), −7, abnormalities of 3q and 11q23; whether alone or in conjunction with intermediate risk or other adverse risk abnormalities. This classification of karyotype was similar to that used in other large multicenter series.16,17

Statistical analyses In the analyses of the outcome of chemotherapy, overall survival (OS) was measured from the first day of remission induction therapy to the date of death or 1 July 1999. Leukemia-free survival (LFS) was measured from the date of CR to relapse or 1 July 1999. In the analyses of the outcome of allogeneic BMT, OS and LFS were measured from the day of transplantation. Patients who received allogeneic BMT were censored on the date of transplantation. Clinical and hematological data, CR rates and relapse rates between AML-TLD and AMLnonTLD groups were compared using the t-test and Fisher exact test. Kaplan–Meier life tables were constructed for survival data and were compared by the log-rank test. Median follow-up was 22 months (1 to 145 months) in the chemotherapy group and 26 months (3 to 114 months) in the allogeneic BMT group. Results

Patient characteristics The characteristics of patients at diagnosis and their clinical outcomes are shown in Table 1. Twenty-eight (23.7%) out of 118 cases were classified as AML-TLD. The frequency of AML-TLD in this series may be higher than that previously

Diagnosis The diagnosis of AML was made according to the FAB classification,14,15 and AML-TLD was classified using the criteria published previously by our group.5 Briefly, dyserythropoietic features were defined as more than 50% dysplastic features in at least 25 erythroblasts, and dysgranulopoietic features included three or more neutrophils with hyposegmented nuclei (pseudo-Pelger–Hu¨et anomaly) and hypogulanular or agranular neutrophils (more than 50% of 10 or more neutrophils). Dysmegakaryopoietic features were defined as three or more megakaryocytes being micronuclear, multiseparated nuclear or large mononuclear. The Central Committee for Morphology of the JALSG reviewed all slides of peripheral blood and bone marrow. CR was defined as normal marrow cellularity with ⬍5% of blast cells with near-normal peripheral blood cell counts (WBC ⬎3 × 109/l, neutrophil counts ⬎1.5 × 109/l and platelet counts 100 × 109/l).

Chromosomes Chromosomes were analyzed in 20 or more cells using standard G banding staining methods. Patients were classified into a favorable, intermediate or adverse risk group based on their karyotypes. The favorable risk group included patients with t(8;21), t(15;17) and inversion (16); whether alone or in conLeukemia

Table 1 therapy

Patient characteristics and clinical outcomes of chemo-

Median age (range) Sex (Male/Female) WBC (×109/l) Hb (g/dl) Platelet (×109/l) Blast of PB (%)a Blast of BM (%)a Auer body (+/−) PO (%) of blast Cytogenetic analysisb Favorable Intermediate Adverse CR rate (%) Relapse rate (%)c

TLD (n = 28)

nonTLD (n = 90)

P value

45 (18苲67) 19/9 23.1 9.6 121 34.6 48.6 13/15 44.3 21 (75%) 0 16 5 75.0 94.1

44 (15苲73) 45/45 26.9 8.9 59 50.5 67.1 62/28 75.7 59 (66%) 37 20 2 88.4 49.3

NS NS NS NS 0.0018 0.0215 0.0004 0.0310 ⬍0.0001

NS 0.0007

NS, not significant; PB, peripheral blood; BM, bone marrow; PO, myeloperoxidase. a Blasts included the leukemic promyelocytes in FAB M3 patients. b Cytogenetic analysis was classified based on our criteria (refer to the text). c Patients who underwent allogeneic BMT in first CR were excluded.


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reported,1,3–5 because FAB-M3 patients were excluded after 1992. AML-TLD was found mainly in FAB-M4 and M6 (nine out of 20 and six of nine cases, respectively), and none in M3 (0 out of 29 cases). One of three in M0, four of 11 in M1, eight of 41 in M2 and 0 of five in M5 were diagnosed as AML-TLD. Between AML-TLD and AML-nonTLD, significant differences were found in platelet count (121 × 109/l vs 59 × 109/l, P = 0.0018), blasts in the peripheral blood (34.6% vs 50.5%, P = 0.0215) and blasts in the bone marrow (48.6% vs 67.1%, P = 0.0004). Fewer patients had Auer body and myeloperoxidase positivity of leukemia blasts was less (P = 0.0310 and ⬍0.0001) in the AML-TLD group. There were no differences in median age, sex ratio, WBC count and hemoglobin level between these two groups. Cytogenetic data were available for 21 (75.0%) AML-TLD patients and 65 (72.2%) AML-nonTLD patients. No AML-TLD patient was found in the favorable risk group and 61.9% had a normal karyotype. All five AML-TLD patients in the adverse risk group had complex karyotypes. Two of the AML-nonTLD patients in the adverse risk group showed 11q23 abnormalities. All of 29 patients with FAB-M3 had t(15;17).

Outcome by chemotherapy The CR rate for chemotherapy in the two groups was similar; 75.0% in the AML-TLD and 88.4% in the AML-nonTLD group (P = 0.1234). But the AML-TLD patients who achieved CR, excluding those who underwent allogeneic BMT in first remission, had a higher relapse rate. Sixteen patients relapsed eventually among 17 AML-TLD patients (94.1%), although 35 of 71 patients (49.3%) relapsed in the AML-nonTLD group (P = 0.0007). The OS and LFS for AML-TLD treated with chemotherapy alone was 18.9% and 0% at 6 years, and both values were significantly lower than for AML-nonTLD (54.3% and 46.3%, respectively) (Figure 1). The differences of OS and LFS were significant even when FAB-M3 patients were excluded from the analysis (data not shown).

Figure 1 Probability of overall survival (a) and leukemia-free survival (b) for AML-TLD and AML-nonTLD patients treated with conventional chemotherapy. Table 2 Patient characteristics and clinical outcomes of allogeneic BMT

Outcome of BMT Table 2 summarizes the characteristics and clinical outcomes of patients who received allogeneic BMT. Median age, sex ratio and the disease status prior to BMT were not different between the two groups. In terms of donor source, two of eight AML-TLD patients received transplants from unrelated donors from the Japan Marrow Donor Program (JMDP). One AML-TLD patient received a transplant from an HLA one locus mismatched, related donor. The remaining five patients received bone marrow from HLA-identical siblings. A similar portion of patients in the two groups received BU + CY as a conditioning regimen or tacrolimus for GVHD prophylaxis. There were no differences in the characteristics of the patients, which can influence the outcome of transplantation. Twenty AML-TLD patients did not receive allogeneic transplantation because of age (11 patients), no donor (seven patients), renal failure (one patient), and refractory leukemia (one patient). Engraftment was achieved in all cases. Two of eight patients (25.0%) in the AML-TLD group and four of 14 patients (28.6%) in the AML-nonTLD group relapsed. Table 3 shows the characteristics of TLD patients prior to conditioning regimen and their outcome. Grade 2–4 acute GVHD occurred in 0 AML-TLD patients and two AML-nonTLD patients, and was fatal in one AML-nonTLD patient in association with inter-

Median age (range) Sex (Male/Female) Disease status (CR1/CR2/Othersa) Donor (related/unrelated) HLA (match/mismatch) Conditioning (BU+CY/TBI-based) GVHD prophylaxis (CsA/FK506) Engraftment (%) Relapse (%)

TLD (n = 8)

nonTLD (n = 14)

30 (18苲45) 5/3 3/0/5

32 (15苲53) 7/7 3/4/7

6/2 7/1 5/3

12/2 12/2 11/3

5/3

12/2

100 25.0

100 28.6

P value



  

–

NS



NS, not significant; GVHD, graft-versus-host disease. a Others included primary induction failure, CR3, 1st relapse with resistance to chemotherapy and more advanced disease.

stitial pneumonia. Three AML-TLD patients and six AMLnonTLD patients died after transplantation; two patients died of relapse of leukemia and one of multi-organ failure in the AML-TLD group, while four died of relapse, one of acute GVHD-associated interstitial pneumonia and one of chronic GVHD in the AML-nonTLD group. The OS after allogeneic Leukemia


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Table 3

No.

Characteristics of AML-TLD patients prior to BMT and their outcome

Age/Sex

FAB

Disease status prior to BMT

1 2 3

24/F 40/M 45/F

M4 M2 M2

Relapse 1 Relapse 1 CR 1

4 5 6 7 8

19/M 24/M 30/F 20/M 39/M

M6 M4 M1 M4 M2

Induction failure Induction failure Relapse 2 CR 1 CR 1

Blast % in BM 2.4 2.2 0.8 9.7 3.2 62.8 2.6 1.6

Cytogenetics

ND 46, XY 46, XX, t(3;11)(p14;p14), del(12)(p11) 46, XY 46, XY 46, XX, t(9;22)(q34;q11) 46, XY 46, XY, del9q-

Outcome

CR/Alive CR/Alive CR/Dead Relapse/Dead CR/Alive Relapse/Dead CR/Alive CR/Alive

BM, bone marrow; F, female; M, male; ND, not done.

BMT was 58.3% and 48.5% at 5 years in the AML-TLD and AML-nonTLD group, respectively and the LFS of the two groups was about the same (75.0% and 63.1%, respectively) (Figure 2). When treated with chemotherapy alone, AML-TLD patients had a similar CR rate but significantly higher relapse rate compared to AML-nonTLD; the OS and LFS were significantly worse than for AML-nonTLD patients. Meanwhile, the relapse rate for AML-TLD patients was similar to that for AML-nonTLD patients after allogeneic BMT. The outcomes of patients who

Figure 2 Probability of overall survival (a) and leukemia-free survival (b) for AML-TLD and AML-nonTLD patients who received allogeneic BMT. Leukemia

received transplantation were comparable between the two groups.

Discussion The characteristics of AML-TLD described in this report were similar to those shown in previous reports; AML-TLD was found frequently in FAB-M4 and M6 subtypes, but was not seen in M3.1,3–5 AML-TLD at diagnosis was comparable to AML-nonTLD in median age, but had a higher platelet count, fewer blasts in the peripheral blood and the bone marrow, fewer patients with Auer body and less myeloperoxidase positivity of leukemic blasts. In cytogenetic analysis, interestingly, more than 60% of AML-TLD patients had a normal karyotype, and none had t(15;17), t(8;21) or inversion (16). No patients with AML-TLD were cytogenetically classified into the favorable risk group. The cytogenetic abnormalities, which are commonly seen in MDS such as number 5 or 7 chromosome abnormalities, were not found in AML-TLD patients in this series. The outcome of chemotherapy alone was significantly worse for AML-TLD than AML-nonTLD; the overall survival and leukemia-free survival of AML-TLD patients at 6 years was 18.9% and 0%, respectively. Seventy-five percent of AMLTLD patients achieved CR with conventional remission induction therapy, but more than 90% of them relapsed in the clinical course even after consolidation therapies. The survival of AML-TLD patients was not improved even with IDA-containing, intensive remission induction therapy and consolidation therapies including mitoxantrone and etoposide. Although the efficacy of high-dose Ara-C for AML-TLD has not been fully examined yet, these results suggest that AMLTLD is one of the AML subtypes refractory to intensive chemotherapy. On the other hand, we found that the outcome of allogeneic BMT for AML-TLD was about the same with that for AMLnonTLD although the number of patients was small in this study. The relapse rate of AML-TLD patients after transplantation was almost equal to that of AML-nonTLD patients. Highly intensive pre-transplant therapy and/or the graft-versus-leukemia effect associated with allogeneic BMT might have brought about a better outcome for AML-TLD patients than conventional chemotherapy alone. This is obviously attributable to the lower relapse rate after allogeneic BMT compared with chemotherapy alone. Therefore, allogeneic BMT during the first remission may be an effective and acceptable therapeutic strategy for AML-TLD patients under 50 years of age if a donor is available.


In a previous report, we compared the clinical data of secondary leukemias transformed from primary MDS (sAML) and AML-TLDs both treated with intensive chemotherapy. We found that the treatment outcome of AML-TLD included a longer survival than that of sAML, though both survival rates were apparently poor; the overall survival of AML-TLD and sAML being 30% and 0% at 3 years, respectively.18 Another study, which reviewed 15 papers dealing with the outcome of sAML treated with intensive chemotherapy, reported that the CR rate was 37% in 231 patients.19 Remission duration of sAML treated with intensive chemotherapy was reported to be much shorter than that of de novo AML by several groups.20–22 These reports and ours demonstrate that both the CR rate and remission duration of sAML treated with intensive chemotherapy are inferior to those of AML-TLD. Meanwhile, the outcome of allogeneic BMT for sAML was also reported to be worse than that for de novo AML.23,24 Prolonged disease-free survival can be expected in only about 20% of patients transplanted for sAML.25 Anderson et al26 also reported that the 5year survival of secondary AML patients was 24.4% after stem cell transplantation. The number of patients who benefit from allogeneic BMT is larger for AML-TLD than sAML because of the better CR rate and the lower ages of the patients.18 Although there is morphological similarity between AML-TLD and sAML, the role of allogeneic BMT in the treatment of these diseases might be quite different. No previous report has compared the outcome of allogeneic BMT between AML-TLD and sAML, however, it seems better for AML-TLD. It is very important to make a correct diagnosis of AML-TLD and to differentiate it from not only AML-nonTLD but also sAML in order to choose the most appropriate treatment strategy including allogeneic BMT. In this report, we conclude that conventional chemotherapy does not provide long survival for patients with AML-TLD, but allogeneic BMT may improve the outcome of AML-TLD. We propose that allogeneic BMT during the first remission be considered for AML-TLD patients if a donor is available.

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Acknowledgements The following institutes participated in this study: Department of Hematology, Nagasaki University Hospital, Nagasaki, Sasebo City General Hospital, Sasebo, Nagasaki-Chuo National Hospital, Ohmura, Nagasaki Municipal Medical Center, Nagasaki and St Francis Hospital, Nagasaki. Allogeneic BMT was performed in Nagasaki University and Sasebo City General Hospital. We are grateful to the JALSG statistical office for providing a portion of the data on AML patients.

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