Relapse of Leukaemia Bone marrow vs extramedullary ... - Nature

Bone Marrow Transplantation (2003) 32, 835–842 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00

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Relapse of Leukaemia Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course K-H Lee1, J-H Lee1, S-J Choi1, J-H Lee1, S Kim1, M Seol1, Y-S Lee1, W-K Kim1, E-J Seo2, C-J Park2, H-S Chi2 and J-S Lee1 1 Division of Oncology-Hematology, Department of Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea; and 2Department of Laboratory Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea

Summary: A total of 118 consecutive adult patients with acute leukemia (78 AML, 36 ALL, and four acute mixed lineage leukemia) underwent allogeneic hematopoietic cell transplantation (HCT) after conditioning with BuCy (n ¼ 113) or a nonmyeloablative regimen of busulfanfludarabine (n ¼ 5). After a median follow-up of 35.8 months (range, 6.4–91.0), 34 patients experienced at least one episode of leukemia relapse. Of 34 initial episodes, 14 (41%) occurred in extramedullary sites, with (n ¼ 8) or without (n ¼ 6) concomitant bone marrow involvement. The median time to relapse in the extramedullary sites was longer than that of relapse in bone marrow only (13.5 vs 6.1 months, P ¼ 0.046). Acute leukemia subtype and disease status at HCT showed an independent predictive value for overall relapse, as well as for extramedullary relapse with or without bone marrow involvement (Philadelphia chromosome positive acute leukemia vs low-risk AML, relative risk 22.68 (95% CI, 2.18– 235.64); other than first CR vs first CR, relative risk 5.61 (95% CI, 1.80-17.51)), but not for bone marrow relapse. Our study suggests that there may be different pathogenetic mechanisms for bone marrow vs extramedullary relapse of acute leukemia after allogeneic HCT. The mode of relapse needs to be investigated in future reports of acute leukemia treated with allogeneic HCT. Bone Marrow Transplantation (2003) 32, 835–842. doi:10.1038/sj.bmt.1704223 Keywords: extramedullary relapse; acute leukemia; allogeneic HCT

ability to decrease leukemia relapse significantly when compared to conventional or high-dose chemotherapy including autologous HCT. This remarkable effect is due to the graft-versus-leukemia (GVL) effect that occurs after allogeneic HCT. Although the overall frequency of acute leukemia relapse is less after allogeneic HCT, a high proportion of extramedullary relapses4–7 in extremely diverse sites has been reported, including the brain,8–11 head and neck,8–10,12 gastrointestinal tract,13 breast,14,15 liver,9 pancreas,16 urogenital tract,13,17 spinal canal and paravertebral tissue,8 bone and periosseous tissue,13,14,18 pleura,14 pericardium,9 peritoneum,19 and skin.20 The median time from allogeneic HCT to acute leukemia relapse was longer in cases with extramedullary relapse with or without bone marrow involvement when compared to cases of bone marrow only relapse.4–6 Uneven effectiveness of the GVL effect in the body of patients was suggested as one of the several possible mechanisms for the increased frequency and wide distribution of extramedullary relapse after allogeneic HCT.4,6 However, other factors, such as nature of the leukemic blasts, status of acute leukemia at HCT, and conditioning regimen may also influence the frequency of extramedullary relapse. This study was undertaken to investigate (1) the frequency of extramedullary relapse in a series of 118 consecutive patients with acute leukemia who underwent allogeneic HCT in a single institution; and (2) whether there are differences between relapse in the bone marrow and extramedullary sites in terms of risk factors and subsequent clinical courses.

Patients and methods Allogeneic hematopoietic cell transplantation (HCT) is now considered part of a standard treatment modality for a significant subset of patients with acute leukemia.1–3 The curative effect of allogeneic HCT is attributable to its

Correspondence: Dr K-H Lee, Department of Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-ku, Seoul 138-040, Korea. E-mail: [email protected] Received 7 February 2003; accepted 16 April 2003

Patients and transplantation procedure Between March 1995 and April 2002, 118 consecutive patients with acute leukemia underwent allogeneic HCT at the Asan Medical Center, University of Ulsan, in Seoul, Korea, and were included in the study. The initial 50 patients who were transplanted up to December 1998 have been described previously.6 Written informed consents for hematopoietic cell collection and transplantation were obtained from patients and donors. Before July 1999, all patients received a BuCy

Extramedullary relapse of acute leukemia after allogeneic HCT

K-H Lee et al

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regimen (busulfan 4 mg/kg/day orally on days 7 to 4 and cyclophosphamide 60 mg/kg/day by intravenous infusion on days 3 to 2)6,21 for conditioning therapy with subsequent infusion of donor marrow cells on day 0. Beginning in July 1999, a nonmyeloablative conditioning regimen of Bu-Flu-ATG (busulfan 4 mg/kg/ day orally on days 7 and 6, fludarabine (Fludaras, Berlex Laboratories, Richmond, CA, USA) 30 mg/m2/day by intravenous infusion on days 7 to 2, antithymocyte globulin (Atgams) 20 mg/kg/day by intravenous infusion on days 5 to 2, and methylprednisolone 2 mg/kg/day by intravenous infusion on days 5 to 2)22 was given to patients who were elderly or who had comorbidity. HLA matching for donor selection was based on serologic typings for HLA-A, B, and C antigens and a molecular typing for HLA-DRB1 antigen. For unrelated donors, six antigens of HLA-A, B, and DRB1 were considered. Patients who were conditioned with the Bu-Flu-ATG regimen received granulocyte colony-stimulating factor-mobilized peripheral blood hematopoietic cells (G-CSF, 10 mg/kg/day subcutaneously for 4 days) on days 0 and 1. None of the hematopoietic cell grafts were T-cell depleted. The regimen for the prophylaxis of GVHD, consisted of cyclosporine 1.5 mg/kg by intravenous infusion every 12 h starting on day 1, which was then switched to an oral dose when oral intake became feasible. In addition to cyclosporine, patients received a short course of methotrexate. Patients who were included in a randomized trial comparing cyclosporine plus methotrexate vs cyclosporine alone for GVHD prophylaxis and who were assigned to the cyclosporine alone arm and the initial three patients who received Bu-Flu-ATG for conditioning did not receive methotrexate. All patients received a daily dose of G-CSF 450 mg intravenously starting on day 0 or day 5 of infusion of donor hematopoietic cells until peripheral blood absolute neutrophil count (ANC) was over 3000 ml. The same dose of G-CSF was administered daily when ANC decreased below 1000 ml. All patients were monitored prospectively for the occurrence of adverse events, including GVHD, regimen-related toxicities, and infections. Acute and chronic GVHD were classified according to the criteria of Przepiorka et al 23 and Sullivan et al,24 respectively. A diagnosis of veno-occlusive disease of the liver (VOD) was made according to the clinical criteria of McDonald et al.25 The severity of VOD was classified into mild, moderate, or severe.26 Beginning in December, 1997, hematopoietic chimerism was analyzed from peripheral blood samples monthly for 3 months, then every 3 months for 2 years after allogeneic HCT. Polymerase chain reaction (PCR)-based procedure utilizing short tandem repeats of DNA was used. Detailed methods of PCR analysis have been described previously.27

Statistics and data analysis The time to leukemia relapse was defined as the interval between HCT and the relapse of leukemia. Median times to relapse between the bone marrow only relapse and the Bone Marrow Transplantation

extramedullary relapse with or without bone marrow involvement were compared using the Mann–Whitney U test. Cumulative incidence curves for leukemia-relapse were plotted using the Kaplan–Meier method and were compared using a log-rank test. For calculation of overall relapse of leukemia, relapse at any site (bone marrow, extramedullary, or both) was considered as an event. For calculation of the time to relapse in the bone marrow only, patients who relapsed in the extramedullary sites with or without bone marrow involvement were censored at the time of relapse. On the other hand, for calculation of the time to relapse in the extramedullary sites with or without bone marrow involvement, patients who relapsed in the bone marrow only were censored at the time of bone marrow relapse. Patients who died due to complications of HCT without a relapse of leukemia were censored at the time of death. For the multivariate analysis, the Cox proportional hazards regression model was used to evaluate the predictive power of various combinations of variables. Post relapse survival in a patient who relapsed with acute leukemia after allogeneic HCT was defined as the interval between the relapse of leukemia and the last follow-up. Post relapse survival curves were plotted using the Kaplan–Meier method and were compared using a logrank test.

Results Patients Table 1 shows the characteristics of the 118 patients who were included in the study. There were 78 with acute myeloid leukemia (AML), 36 with acute lymphoblastic leukemia (ALL), and four with acute mixed lineage leukemia. The median ages of the patients were 33.5 years (range, 16–57) for AML, 30 years (range, 16–57) for ALL, and 26.5 years (range 20–38) for acute mixed lineage leukemia. Of the 78 patients with AML, 26 had normal cytogenetics, nine t(8;21), six t(15;17), and two inv(16) at the time of diagnosis. When we assigned the patients with AML according to the Southwest Oncology Group (SWOG) criteria,28 17 showed favorable, 28 intermediate, 15 unfavorable, and 10 undetermined risk status. Of the 36 patients with ALL, 26 patients showed pre-B cell type and eight T-cell type on immunophenotyping. A total of 10 patients showed the Philadelphia chromosome (Ph) (eight ALL and two acute mixed lineage leukemia). In all, 65 of the 78 AML patients, 23 of the 36 ALL patients, and two of the four acute mixed lineage leukemia patients were in their first complete remission (CR) status at the time of HCT. A majority of patients received the BuCy regimen for conditioning. Five (four AML and one ALL) patients received the nonmyeloablative regimen of Bu-Flu-ATG for conditioning. A total of 27 patients (13 AML, 12 ALL, and two acute mixed lineage leukemia) received hematopoietic cells from unrelated donors.

Extramedullary relapse of acute leukemia after allogeneic HCT K-H Lee et al

837 Table 1

Patient and transplant characteristics

Characteristics

AML (n ¼ 78)

ALL (n ¼ 36)

AmixL (n ¼ 4)

Age (years), median (range)

33.5 (16–57)

30 (16–57)

26.5 (20–38)

Sex Male Female

39 39

19 17

2 2

WBC count at diagnosis (/ml) Less than 4000 4 000–30 000 Over 30 000

22 29 27

8 20 8

1 1 2

Peripheral blood % blast at diagnosis Less than 25 25–75 Over 75

28 27 23

11 16 9

1 2 1

0

2

0

Extramedullary disease at diagnosis FAB or immunophenotypic classification

Cytogenetic findings

M0: 5 M1: 17 M2: 31 M3: 6 M4: 15 M5: 2 M6: 2 Not done: 8 Normal: 26 inv 16: 2 t(8;21): 9 t(15;17): 6 +8 or +6: 2 del (9q): 3 abn 11q: 3 del (5q): 1 t(6;9): 3 Others: 15

Pre-B cell: 26 T cell: 8 Unknown: 2

Not done: 3 Normal: 11 t(9;22): 8 del (5q): 2 del (7q): 1 –7: 1 t(1;19): 1 t(14;14): 1 Hyperdiploid: 2 Others: 6

Normal: 1 t(9;22): 2 t(9;11): 1

Interval from diagnosis to HCT (months) Less than 4 4–12 over 12

40 33 5

8 19 9

Disease status at HCT Untreated Refractory First CR First relapse Second CR 4Second CR

1 1 65 4 5 2

23 3 6 4

Conditioning regimen/hematopoietic cell source BuCy/bone marrow BuFluATG/peripheral blood

74 4

35 1

32.5 (13–55)

30 (16–55)

40 38

24 12

4

Type of HCT Sibling, HLA full match Unrelated, HLA match Unrelated, one locus mismatch

65 12 1

24 10 2

2 1 1

Bone marrow cell dose, median (range) Mononuclear cells ( 108/kg) CD34+ cells ( 106/kg)

0.92 (0.30–3.10) 3.40 (0.01–15.0)

0.85 (0.32–2.15) 2.48 (0–13.93)

GVHD prophylaxis CSA alone CSA+MTX

14 64

6 30

Donor age (years), median (range) Donor sex Male Female

2 2

1 2 1

4 0 27.5 (26–53)

0.74 (0.60–1.14) 2.68 (0.89–6.60) 0 4

AmixL ¼ acute mixed lineage leukemia; CSA ¼ cyclosporine; MTX ¼ methotrexate.

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Frequency of extramedullary relapse with or without bone marrow involvement After the median follow-up time of 35.8 months (range, 6.4–91.0) in surviving patients, 34 of 118 patients experienced at least one episode of acute leukemia relapse. Of those 34 initial episodes of acute leukemia relapse, 14 (41%) were in extramedullary sites with or without concomitant bone marrow involvement (Table 2). Six patients (UPNs 14, 18, 62, 125, 159, and 204) showed relapses in extramedullary sites only, without bone marrow involvement. The involved extramedullary sites were the brain (pons and peri-leptomeningeal cortex), uterus/urinary bladder, skin, spinal canal (intradural and epidural masses, L3-S1), breast, and soft tissue (popliteal fossa). Eight patients (UPNs 23, 59, 67, 71, 73, 93, 118, and 165) relapsed in extramedullary sites (bones, peri-osseous soft tissue, intestine, mediastinum/pleura, breast, pancreas, leptomeninges, and skin) along with bone marrow involvement. A total of 20 patients (59%) relapsed in the bone marrow only. The median time to relapse in the bone marrow only was 6.1 months (range, 2.0–83.6), while the median time to relapse in the extramedullary sites with or without bone marrow involvement was 13.5 months (range, 4.9–49.9, P ¼ 0.046, Figure 1).

Risk factors for overall relapse, relapse in the bone marrow only, and extramedullary relapse with or without bone marrow involvement, univariate analysis The variables considered for univariate analysis included age, sex, diagnosis (AML vs ALL), acute leukemia subtype, white blood cell count at diagnosis, extramedullary disease at diagnosis, interval from diagnosis to HCT, disease status at HCT, conditioning regimen, donor age, sex mismatched HCT, sibling vs unrelated donor HCT, GVHD prophylaxis, chimerism at 1 month, and acute and chronic GVHD. The variables that showed significant correlation with overall relapse of acute leukemia were acute leukemia subtype (P ¼ 0.028) and disease status at HCT (Po0.001). The subtype that showed the highest rate of leukemia relapse was Ph-positive acute leukemia (5/10, 5-year cumulative incidence of 100%), followed by high-risk AML (6/15, 58%). Pre-B-cell ALL without Ph and T-cell ALL showed similar rates of relapse (7/18, 52% and 3/8, 52%, respectively). Low-risk AML showed the lowest rate of relapse (3/17, 21%). As per disease status at HCT, 21 of 90 (35%) patients who were transplanted during their first CR relapsed, while 13 of 28 (68%) patients who were transplanted during other status of the disease relapsed. Other variables that showed a trend for correlation with overall relapse of acute leukemia after allogeneic HCT were the diagnosis of AML vs ALL (31 vs 57%, P ¼ 0.091), GVHD prophylaxis with CSA only vs CSA plus methotrexate (16 vs 44%, P ¼ 0.205), acute GVHD (none vs grades I–II vs grades III–IV; 49 vs 17 vs 20%, P ¼ 0.215), and chronic GVHD (none vs limited vs extensive; 42 vs 44 vs 21%, P ¼ 0.199). Further univariate analysis was performed with separate consideration of relapse in the bone marrow only (n ¼ 20) and extramedullary relapse with or without bone marrow Bone Marrow Transplantation

involvement (n ¼ 14). Acute leukemia subtype (P ¼ 0.005) and disease status at HCT (Po0.001) showed significant correlation with extramedullary relapse with or without bone marrow involvement. The subtype that showed the highest rate of extramedullay relapse was Ph-positive acute leukemia (3/10, 5-year cumulative incidence of 100%), followed by high-risk AML (4/15, 50%). Low-risk AML showed the lowest rate of extramedullary relapse (1/17, 9%). Seven of 90 patients (17%) who were transplanted during their first CR experienced extramedullary relapse while seven of 28 patients (51%) who were transplanted during other status of leukemia experienced extramedullary relapse. On the other hand, none of the variables showed significant correlation with relapse in the bone marrow only.

Risk factors for overall relapse, relapse in the bone marrow only, and extramedullary relapse with or without bone marrow involvement, multivariate analysis The variables that showed a significance level of P-value o0.2 on univariate analysis, as well as the patient’s age and sex were considered in the variable selection process. For overall acute leukemia relapse, acute leukemia subtype (Ph-positive acute leukemia vs low-risk AML, relative risk 13.00 (95% CI, 2.43–69.63)) and disease status at HCT (other than first CR vs first CR, relative risk 3.03 (95% CI, 1.32–6.98)) were independent variables that showed significant correlation. The same variables showed significant independent correlation with extramedullary relapse, that is, acute leukemia subtype (Ph-positive acute leukemia vs low-risk AML, relative risk 22.68 (95% CI, 2.18–235.64)) and disease status at HCT (other than first CR vs first CR, relative risk 5.61 (95% CI, 1.80–17.51)). None of the variables showed independent correlation with relapse in the bone marrow only.

Clinical course after relapse of acute leukemia after allogeneic HCT Prognosis of the patients who relapsed after allogeneic HCT was poor, with a median survival time of 7.8 months (range, 0.6–58.8 þ ) after the relapse of acute leukemia. Seven patients are surviving without evidence of acute leukemia 7.8–58.8 months after relapse. A total of 14 patients who experienced extramedullary relapse with or without bone marrow involvement were treated with various modalities (Table 2) including combination chemotherapy with subsequent donor leukocyte infusion (DLI) and local radiation therapy (six patients), combination chemotherapy with DLI (three patients), local radiation therapy (two patients), oral administration of imatinib mesylate (one patient), cyclosporine withdrawal (one patient), and supportive care (one patient). Two patients (UPNs 67 and 125) are surviving without evidence of acute leukemia 15.6 and 37.8 months after relapse. In all, 14 of 20 patients who experienced acute leukemia relapse in the bone marrow only were treated with combination chemotherapy with subsequent DLI. A total of 10 patients achieved CR. Of those 10 patients, four are surviving without acute leukemia relapse 7.8–58.8 months

Table 2 UPN

Summary of clinical courses of 14 patients with acute leukemia who relapsed at the extramedullary sites with or without bone marrow involvement after allogeneic HCT Age/ sex

Dx, cytogenetics

Status at HCT

Donor

Post HCT clinical courses before relapse VOD

aGVHD

GVHD

Mo from HCT to relapse

Sites of relapse

32/M

L2, pre-B t(9;22)

CR1

27/F, HLA iden sibling

Sev

None

None

49.9

CNS (right lobe of pons)

18

40/F

M4, inv (16)

CR1


Mod

None

Lim

26.9

23

17/F

M2, normal

CR1

20/M, HLA iden sibling

None

None

Ext

34.4

59

21/M

M1, del (9q)

CR1

Mild

None

None

17.0

62

35/F

M4, del (1p), t(11;17)

CR1

18/M, HLA iden sibling 37/F, HLA iden sibling

None

None

None

5.0

Huge mass involving uterus and bladder wall Blood/marrow+ right mandible and soft tissue Blood/marrow+ intestines Skin

67

19/F

M1, dup (3q)

CR2


Mild

Gr I

None

16.9

71

36/M

L2, T cell, trisomy 21

CR1

40/M, HLA iden sibling

Mod

None

None

12.3

73

20/M

L1, pre-B t(9;22)

CR1


None

None

Ext

11.8

93

31/F

L2, pre-B complex ab

CR2


Mod

None

None

14.6

118

21/M

L1, pre-B complex ab

REL2

26/M, mat unrel donor

Mod

Gr III

Ext

125

18/M

M1, +22,

CR2

23/M, mat unrel donor

None

None

None

20.1

159

23/F

M2, +6,

REL1


None

None

None

8.6

165

42/F

M4, complex ab

REL1

None

None

None

4.9

Blood/marrow+skin

204

28/M

ALL, pre-B t(9;22)

REL2

26/M, mat unrel donor 35/M, HLA iden sibling

None

None

None

9.4

CNS (peri-leptomeningeal cortex)

9.3

lower

Blood/marrow+skin and bones (ulna, femur) Blood/marrow+ mediastinum/pleura Blood/marrow+ left distal radius with soft tissue Blood/marrow+ left breast, pancreas, multiple bones Blood/marrow+ CNS (leptomeninges) Intradural and epidural masses, L3-S1 Both breasts, skin, right popliteal fossa

Current status (post HCT months)

Whole brain irradiation, 2000 cGy (PR) Supportive care

Alive (60.6)

Chemotx+DLI+ local XRT, 4000 cGy (CR) Chemotx+DLI (persistent) Cyclosporine withdrawal (persistent) Chemotx+DLI+ local XRT (CR) Chemotx+DLI+ local XRT 2200 cGy (CR) Chemotx+DLI+ local XRT, 3000 cGy (CR) Chemotx+DLI+ local XRT (CR)

Died with leukemia (27.7) Died with leukemia (62.9) Died with leukemia (17.6) Died with leukemia (14.4) Alive (54.7)

and

NED

Died with leukemia (18.4)


Died with leukemia (16.9) Died with sepsis and GVHD (28.3)

Chemotx+DLI+ IT MTX (not evaluable) Local XRT, 2000 cGy (CR)

Died (11.7)

with

sepsis

Alive (35.8)

and

NED

Chemotx+DLI+ local XRT, 3000 cGy (CR) Chemotx+DLI (not evaluable) Gleevec for 61 days (persistent)

Died with leukemia (20.4) Died with sepsis (5.9) Alive with CNS leukemia (15.1)

CR1 ¼ first complete remission; CR2 ¼ second complete remission; REL1 ¼ first relapse; REL2 ¼ second relapse; HLA iden sibling ¼ HLA identical sibling; mat unrel donor ¼ HLA matched unrelated donor; XRT ¼ radiation therapy; sev ¼ severe; gr ¼ grade; mod ¼ moderate; lim ¼ limited; ext ¼ extensive; Chemotx ¼ chemotherapy; DLI ¼ donor leukocyte infusion; NED ¼ no evidence of disease.

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14

Treatment after relapse (outcome)


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840

A (83.60)

B

0

12

24

36

48

Month Figure 1

Times to relapse of acute leukemia after allogeneic HCT were plotted for relapse in the bone marrow (a, n ¼ 20) and extramedullary relapse with or without bone marrow involvement (b, n ¼ 14). Noteworthy, the median time to relapse in the bone marrow was shorter than the median time to relapse in the extramedullary sites with or without bone marrow involvement (6.1 vs 13.5 months, P ¼ 0.046).

after relapse. Five patients were treated with combination chemotherapy. Of two patients who achieved CR after combination chemotherapy, one is surviving without evidence of leukemia 10.8 months after relapse. The results of univariate analysis showed that patient age (less than 25 years vs 25–40 vs over 40; 16 vs 28 vs 0% surviving, Po0.001) and interval between HCT and acute leukemia relapse (less than 6 months vs 6–18 vs over 18; 8 vs 17 vs 36% surviving, P ¼ 0.023) were significant variables that predicted post relapse survival of the patients. There was no significant difference in post relapse survival between patients with bone marrow only relapse and patients with extramedullary relapse with or without bone marrow involvement.

Discussion The frequency of extramedullary relapse of acute leukemia after allogeneic HCT reported in the literature varies widely. Retrospective data from a registry reported 20 patients among 3071 patients with AML (0.7%) as having extramedullary relapse.8 In our series of 118 patients with acute leukemia who underwent allogeneic HCT, 14 patients (5-year cumulative incidence of 23%) experienced an initial relapse involving extramedullary sites with or without bone marrow involvement. Extramedullary relapse with or without bone marrow involvement accounted for 41% (14/34) of overall initial relapse. Our results are consistent with other recent data that reported an overall frequency of extramedullary relapse ranging from 5 to 12% of all patients7,20 and the percentage of extramedullary relapse with or without concomitant relapse in the bone marrow among the overall relapse of 27–50%.5–7 The discrepancy of reported frequency of extramedullary relapse may be due to under-reporting in retrospective registry data and the longer survival of patients in recent series due to less patients dying of transplantation-related causes. Bone Marrow Transplantation

Factors that are known to predict relapse of acute leukemia after allogeneic HCT include disease status at the time of transplant, T-cell depletion of the hematopoietic cell graft, presence of GVHD, and leukemia subtype.1–3,28– 30 When we analyzed various pre and post transplant variables in our series of patients, acute leukemia subtype and disease status at HCT were significant independent prognostic factors for overall relapse of acute leukemia. Acute and chronic GVHD failed to show significant correlation, although patients without GVHD tended to show a higher relapse rate. Further analysis with separate consideration of the different mode of relapse (bone marrow vs extramedullary) showed that acute leukemia subtype and disease status at HCT showed significant correlation with extramedullary relapse with or without bone marrow involvement, but not with bone marrow only relapse. This finding suggests that known prognostic factors for acute leukemia relapse after allogeneic HCT affect bone marrow relapse and extramedullary relapse to different degrees. Furthermore, the findings in our study, as well as those of others,4,5 which showed that the median time to relapse of acute leukemia in the bone marrow was shorter than that of extramedullary relapse with or without bone marrow involvement suggest that different pathogenetic mechanisms play roles in relapses in the bone marrow and in the extramedullary sites. The high extramedullary relapse rate of acute leukemia in our study may be related to the low plasma level and poor tissue penetration of orally administered busulfan31,32 that was used in our study. One randomized study reported a higher incidence of relapse of AML among patients who received the BuCy regimen as opposed to the cyclophosphamide-total body irradiation (TBI) regimen,33 while another study failed to show such a difference.34 The nature of relapse of leukemia was not stated in either study. Further prospective studies with larger number of patients and separate end points for bone marrow vs extramedullary relapse are needed to ascertain the relative effects of the different conditioning regimens (TBI containing vs non-TBI containing; oral busulfan vs intravenous busulfan;35 and myeloablative vs nonmyeloablative conditioning regimen), the different degree of GVL/GVHD effects, and the characteristics of the leukemic cells in the different modes of relapse of acute leukemia after allogeneic HCT. Eventually, different therapeutic strategies for the prevention of different modes of relapse of acute leukemia after allogeneic HCT may become apparent. Once acute leukemia relapse occurs after allogeneic HCT, the prognosis is poor, with a median post relapse survival time of 7.8 months in our series of patients. The age of patients and the interval between HCT and relapse were the significant prognostic factors. The number of patients in our study was too small to detect other potentially important variables that might have prognostic significance (i.e., mode of relapse after allogeneic HCT). In conclusion, our study showed a high frequency of extramedullary relapse of acute leukemia after allogeneic HCT after conditioning with a non-TBI containing preparative regimen (41% of all initial relapses). Extramedullary relapse occurred later than bone marrow relapse. Acute leukemia subtype and disease status at HCT were


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significant independent predictors of extramedullary relapse but not of bone marrow relapse. We propose a separate consideration of different modes of relapse of acute leukemia for future studies reporting the results of acute leukemia treated with allogeneic HCT.

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