Allografting Relapse of chronic myeloid leukemia after ... - Nature

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Allografting Relapse of chronic myeloid leukemia after allogeneic stem cell transplantation: outcome and prognostic factors. The Chronic Myeloid Leukemia Subcommittee of the GETH (Grupo Espanõl de Trasplante Hemopoye´tico) C Martı´ nez, V Gomez, JF Toma´s, R Parody, A Sureda, G Sanz, C Can˜izo, JL Dı´ ez and C Boque´, for the CML Subcommittee of the Spanish Group of Hematopoietic Transplantation (Grupo Espanõl de Trasplante Hemopoye´tico, GETH) Bone Marrow Transplantation Section, Hematology Department, Hospital Clıńic, Barcelona, Spain

Summary: In order to analyze the outcome of patients with chronic myeloid leukemia (CML) who relapse after allogeneic stem cell transplantation (SCT), we investigated data from 107 patients reported to the Spanish Registry, GETH. In all, 93 (87%) patients were treated after relapse; 36 out of 49 that failed to achieve a response received a second relapse-treatment, and seven a third one. At the last follow-up, the number of patients in molecular or cytogenetic remission was 29 and 13, respectively. Overall survival and progression-free survival after relapse were 53.6% (95% CI: 42.9–64.2) and 52% (95% CI: 41–63) at 5 years, respectively. In multivariate analysis, survival was significantly related to CML phase at relapse (cytogenetic or chronic phase vs advanced phases) and time from transplant to relapse (o1 vs X1 year). Patients with no adverse factors had a better survival compared with patients with one or two adverse features (65 vs 35 vs 0%, respectively). We conclude that a significant proportion of CML patients that relapse after transplantation can regain complete and long-lasting remissions with one or more salvage therapies. Disease stage at relapse and time from transplant to relapse should be taken into account when comparing results of different salvage treatments. Bone Marrow Transplantation (2005) 36, 301–306. doi:10.1038/sj.bmt.1705063; published online 20 June 2005 Keywords: chronic myeloid leukemia; relapse; allogeneic transplantation

leukemia (CML).1–3 One of the major causes of treatment failure after SCT is relapse. Phase of the disease at transplantation and T-cell depletion of the graft are the main factors that influence the risk of relapse. Thus, the probability of relapse increases to 40–60% for patients transplanted in advanced phase and for those grafted during chronic phase that receive manipulated marrow cells.4–6 A number of approaches have been used to treat patients with CML in relapse after transplantation depending on disease phase, presence of graft-versus-host disease (GvHD), performance status of the patient, use of T-cell depletion, and center policy. Standard therapies for CML, a-interferon (a-IFN), donor lymphocyte infusion (DLI), second allogeneic SCT, and, more recently, imatinib have all been used with variable degrees of success.7–14 In a previous retrospective study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT), based on 500 CML patients who relapsed after an allogeneic SCT, overall survival was 34% at 5 years.15 A number of prognostic factors were identified and allowed the authors to differentiate between different risk groups for outcome after relapse. Thus, survival decreased from 42 to 0% depending on the cumulative number of risk factors: time from diagnosis to transplant, disease phase at SCT, disease phase at relapse, time from transplant to relapse, and donor type. We analyzed the outcome of a series of patients mostly relapsed after 1990 and treated in the pre-imatinib era. In this analysis, we were specifically interested in the pattern of therapeutic management of the relapse and in the evaluation of the risk factors for survival.

Allogeneic stem cell transplantation (SCT) is currently the only curative treatment for patients with chronic myeloid

Patients and methods Correspondence: Dr C Martı´ nez, Bone Marrow Transplantation Section, Hematology Department, Hospital Clı´ nic, Villarroel 170, 08036 Barcelona, Spain; E-mail: [email protected] Received 20 December 2004; accepted 24 April 2005; published online 20 June 2005

We conducted a retrospective analysis on behalf of the CML Subcommittee of the Spanish Group for Hematopoietic Transplantation (Grupo Espanõl de Trasplante Hemopoye´tico, GETH). As of December 2002, 143 out of

Relapse of CML after allogeneic SCT C Martıńez et al

302

836 CML patients in the Spanish registry, who had relapsed after an allogeneic SCT from an HLA-identical sibling donor or from an HLA-matched unrelated donor, were identified. Eight centers contributed patients to the study. Detailed information was asked about the type of relapse, therapy for relapse, response to therapy, and clinical outcome. Complete information was collected from a total of 107 out of 143 reported relapses that were finally included in the study. Transplants were performed between January 1, 1984 and December 31, 2002. In total, 59 patients were male and 48 female; the median age at transplantation was 33 (range, 13–59) years. Source of progenitor cells was the bone marrow in 80 patients and peripheral blood in 27. Relapse after transplant was defined as the appearance either of Philadelphia-positive (Ph þ ) metaphases on cytogenetics performed on bone marrow cells or of hematological signs of the disease that were subsequently confirmed by cytogenetics. Criteria for molecular relapse and CML relapse monitoring practices after transplantation were not specifically requested from each transplantation center. Reported treatment options included single-agent or intensive multidrug chemotherapy, a-IFN, DLI, imatinib, second SCT, and palliative care. The doses and schedules for chemotherapy, a-IFN, DLI, and imatinib were not specified. A second SCT was defined as the reinfusion of donor cells following a myeloablative-conditioning regimen. Response to treatment was defined as the achievement of partial (presence of 1–99% of Ph þ metaphases in conventional cytogenetic analysis) or complete (absence of Ph þ metaphases) cytogenetic remission, or molecular remission (no presence of bcr-abl transcripts by RTPCR). Interval from diagnosis of relapse to first relapse treatment, the sequence of treatments, and the response to each specific treatment were also reported. The following features thought to be potential prognostic factors for survival were included in the analysis: interval from diagnosis to first SCT (o1 year vs X1 year), disease phase at transplant (first chronic phase (CP) vs more advanced phases), source of stem cells (bone marrow vs peripheral blood), T-cell depletion (no vs yes), EBMT score at transplant (0–2 vs 3–6),16 interval from SCT to relapse (o1 vs X1 year), disease phase at relapse (cytogenetic vs CP; cytogenetic or CP vs more advanced phases), interval from relapse to treatment (o4 vs X4 months; and o6 vs X6 months), and chronic GvHD before relapse (no vs yes).

Statistical methods Survival was calculated from date of first evidence of relapse to death or to last follow-up according to the Kaplan–Meier method and compared by the two-sided log rank test. A Cox proportional-hazards model was constructed to detect independent predictors of death. The association between variables was analyzed by the chi-square test, with the appropriate degrees of freedom. The analysis was performed with SPSS software (Chicago, IL, USA). Bone Marrow Transplantation

Results Patient characteristics, pattern, and treatment of relapse Most patients (87%) had been transplanted after 1990. At transplant, 88 (82.2%) patients were in first CP, 10 (9.3%) in second CP or accelerated phase (AP), and nine (8.4%) in blast crisis (BC). The majority of patients were transplanted from an HLA-identical sibling donor. The median time from diagnosis to SCT was 12 (range 2–97) months. T-cell depletion of the graft and absence of chronic GvHD after SCT, both factors known to be associated with a higher risk of relapse after SCT, were reported in 38 and 80% of the patients, respectively (Table 1). Median time from SCT to relapse was 15 (range 1–97) months and seven patients relapsed after 5 years post transplant. The disease stage at relapse was cytogenetic

Table 1

Patient characteristics and pattern of relapse

Patient characteristics Patient age (median and range, years)

Total number 33 (13–59)

Patient sex Male Female

59 48

Interval from diagnosis to SCT o1 year X1 year NA

48 52 7

Disease phase at SCT First chronic phase 4First chronic phase

88 19

T-cell-depleted SCT Yes No

34 73

Chronic GvHD after SCT No Limited Extensive NA

72 13 6 16

Interval from SCT to relapse o1 year X1 year NA

45 58 4

Date at relapse o 1990 1990–1995 X1996

6 29 72

Disease phase at relapse Molecular Cytogenetic Hematological CP Hematological AP-BC NA

4 40 27 35 1

Interval from relapse to treatment (median and range, months)

4 (0–51)

SCT ¼ stem cell transplantation; NA ¼ not applicable or unavailable; GvHD ¼ graft-versus-host disease; CP ¼ chronic phase; AP ¼ accelerate phase; BC ¼ blast crisis.


303

Overall outcome Overall, 50 patients died from relapse. Causes of death were disease progression (n ¼ 29), infection (n ¼ 9), GvHD (n ¼ 4), transplant-related mortality (n ¼ 3), solid neoplasia (n ¼ 1), myocardial infarction (n ¼ 1), chronic hepatitis (n ¼ 1), and hemorrhage (n ¼ 2). Five patients died in response (four cytogenetic and one molecular responses) due to complications after savage therapy. The Kaplan–Meier estimated overall survival and progression-free survival after relapse were 53.6% (95% CI: 42.9–64.2) and 52.2% (95% CI: 41.0–63.4) at 5 years, respectively (Figure 1). At the last follow-up among 57 survivors, 13 patients had a cytogenetic response (four partial and nine complete cytogenetic response) and 29 had a molecular response. In total, 60% of the patients alive in cytogenetic or molecular remission have received one type of relapse-treatment, 28% two, and 12% three. The median follow-up of these patients was 43 (range 1–136) months and in 72% of them the interval from relapse to last follow-up exceeded the interval from SCT to relapse. The probability of survival according to the type of first relapse-treatment was: a-IFN 52.7%, DLI 80.4%, second SCT 25%, imatinib 50%, hydroxyurea 0%, and

a 1.0 0.9

Probability of survival

0.8 0.7 0.6 0.5 0.4 0.3 53.6% (95% CI: 42.9–64.2) at 5 years

0.2 0.1 0.0 0

1

2

3 4 5 6 7 8 9 Years after transplantation

10 11 12

b 1.0 Probability of progression free survival

relapse in 40 patients (37.4%), hematological relapse in CP in 27 (25.2%), and hematological relapse in advanced phase (AP or BC) in 36 (33.6%). Four relapses (3.7%) were reported as molecular relapse; however, any of them was treated before the progression to cytogenetic level, so all of them were included in the study. Disease stage at relapse was significantly correlated with that at time of SCT (Po0.0001). Patients who relapsed along the first year after transplant had been transplanted in more advanced phases of the CML in comparison to patients who relapse later (52 vs 17%, respectively, Po0.001). After relapse, 93 patients (87%) received one to three types of treatment. Treatment was delayed until progression of the disease in eight cases: four molecular relapses progressed to a cytogenetic relapse and four cytogenetic relapses progressed to hematological relapse. In all, 13 patients, all of them in BC relapse, received only palliative care, and one patient died early without treatment. Only four patients received hydroxyurea alone not followed by other type of therapy. First relapse-treatment, preceded or not by hydroxyurea, consisted of a-IFN in 29 patients (18 cytogenetic, nine CP, and two AP relapses), DLI in 38 patients (24 cytogenetic, nine CP, and five BC relapses, in combination with multidrug chemotherapy), second SCT not preceded by DLI in five patients (one CP and four BC relapses), imatinib alone in two and in combination with DLI in two patients (three cytogenetic and one CP relapses), and multidrug chemotherapy in 12 patients (AP-CB relapses). Of 49 patients that did not achieved any type of response (hematological, cytogenetic, or molecular) to first relapse-therapy, 36 received a second relapse-treatment: a-IFN was given in four patients, DLI in 13, second SCT in seven, imatinib in 10, and palliative care in two. Finally, seven patients received a third relapsetreatment: a-IFN was given in two patients, second SCT in two, and imatinib in three.

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

52.2% (95% CI: 41–63.4) at 5 years

0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Years after transplantation Figure 1 (a) Probability of survival from relapse at 5 years. (b) Probability of progression-free survival from relapse at 5 years.

chemotherapy or palliative care 0% (Table 2). Differences in survival between different types of treatments may reflect the differences in prognosis according to the disease phase at relapse. Most patients relapsing in cytogenetic or hematological CP received a-IFN or DLI, whereas those relapsing in advanced phases received multidrug chemotherapy or palliative care. No differences were found between a-IFN and DLI as first relapse-therapy in the number of responses or in the survival (P ¼ 0.3). However, the small number of patients receiving second SCT, imatinib, or hydroxyurea precluded an accurate analysis of the differences in the probabilities of response or survival between these groups of patients. The prognostics factors for survival identified in univariate analysis were: time from diagnosis to SCT (o1 year 64% vs X1 year 27%, P ¼ 0.07), time from transplant to relapse (o1 year 18% vs X1 year 55%, Po0.0001), disease Bone Marrow Transplantation


304 1.0 0.9 0.8 Probability of survival

stage at relapse (cytogenetic or CP 59% vs AP and BC 5%, Po0.0001), and T-cell depletion of the graft (no 33% vs yes 51%, P ¼ 0.015). Chronic GvHD after transplantation did not influence the probability of survival after relapse (31% vs 31 vs 25% for absence of GvHD, limited GvHD, and extensive GvHD, respectively, P ¼ 0.99). In the final model of the Cox multivariate analysis of survival, only two variables remained significant: disease stage at relapse and time from transplant to relapse (Table 3). Survival after hematological relapse in CP was not statistically different from that after cytogenetic relapse (Figure 2). Patients who relapsed after SCT in cytogenetic or CP did better than those relapsing in more advanced phases (Figure 3a). The

Cytogenetic relapse, 61.5%

0.7 0.6

Chronic phase relapse, 49.8%

0.5 0.4 0.3

Accelerated phase relapse, 25%

0.2 Table 2 Probability of survival according to the type of first relapse treatment Type of first relapse treatment

n

Overall survival (95% CI)

a-IFN DLI Second SCT Imatinib Hydroxyurea Chemotherapy or palliative care

29 38 5 4 4 25

52.7% 80.4% 25% 50%

(28.3–77.1) (67.0–93.8) (3.4–46.6) (14.6–85.4) 0% 0%

a-IFN ¼ a interferon; DLI ¼ donor lymphocyte infusion; SCT ¼ stem cell transplantation.

0.1

Blastic phase relapse, 0%

0.0 0

1

2


10 11 12

Figure 2 Probability of survival according to the CML stage at relapse.

outcome of patients who relapse along the first year after transplantation was poorer than those who relapse later (Figure 3b). Patients with no adverse factors had a significantly better survival compared with patients with one or two adverse features (65 vs 35 vs 0%, respectively (Po0.0001)) (Figure 4).

Table 3 Univariate and multivariate analysis (Cox regression analysis) of prognostics factors for survival after relapse Risk factors

Univariate analysis

Multivariate analysis

Time from diagnosis to SCT o1 vs X1 year

0.07

NS

Disease phase at SCT CP vs advanced phases

NS

—

Source of stem cells Bone marrow vs peripheral blood

NS

—

0.015

NS

EBMT score at transplant 0–2 vs 3–6

NS

—

Time from SCT to relapse o1 vs X1 year

o0.0001

o0.0001 RR 3.2 (95% CI 1.5–6.9)

Disease phase at relapse Cytogenetic or CP vs AP or BC

o0.0001

0.003 RR 0.1 (95% CI 0.05–0.2)

Time from relapse to treatment p6 vs 46 months

NS

—

Chronic GvHD after SCT No vs yes

NS

—

T-cell depletion No vs yes

SCT ¼ stem cell transplantation; CP ¼ chronic phase; EBMT ¼ European Blood and Marrow Transplantation Group score; RRrisk ratio; CI ¼ confidence interval; AP ¼ accelerate phase; BC ¼ blast crisis; GvHD ¼ graft vs host disease. Bone Marrow Transplantation

Discussion Our results show that a significant proportion of patients with CML who relapse after SCT can achieve second complete remissions after salvage treatment and a prolonged survival. In a previous retrospective study of the Chronic Leukemia Working Party of the EBMT, survival after relapse was significantly related to five factors: time from diagnosis to transplant, disease phase at transplant, disease stage at relapse, time from transplant to relapse, and donor type.15 Overall survival of this series was 34% at 5 years. In the present study, the probability of survival and the probability of progression-free survival after relapse were 53.6 and 52.2% at 5 years, respectively. The majority of patients had been transplanted in first CP from an HLA-identical sibling donor after 1990 and received a-IFN and/or DLI after relapse, all of them factors that might account for the improved outcome for this series of patients. Similarly to a previous observation, survival after relapse was significantly related to disease stage at relapse and interval from SCT to relapse. Thus, patients who relapse early after transplant (o1 year) in advanced phase of the disease particularly have a very bad outcome. Although the prognostic value of the disease phase at relapse should be interpreted with caution since this variable could also be related to the methods of disease monitoring after transplant, this is the second study that shows its prognostic value in a multivariate analysis. This observation should encourage accurate monitoring of disease after


305 1.0

a 1.0 0.9

0.7 0.6 0.5 0.4

P < 0.0001

0.3 0.2

Accelerate phase and blastic phase relapses, 5%

0.1

0.8 Probability of survival

Probability of survival

0.8

0 risk factors, 65%

0.7 0.6 0.5

1 risk factors, 35%

0.4 0.3 0.2 0.1

0.0 0

1

2


10 11 12

2 risk factors, 0%

0.0 0

1

2


10 11 12

Figure 4 Probability of survival from relapse according to the cumulative

b 1.0

number of adverse factors (Cox regression analysis): adverse features include advanced disease stage at relapse (accelerated phase and blast crisis) and interval from SCT to relapse higher than 12 months.

0.9 SCT-relapse interval > 12 months 54.9%

0.8 Probability of survival

0.9

Cytogenetic and chronic phase relapse, 59.2%

0.7 0.6 0.5 0.4 P < 0.0001

0.3 0.2

SCT-relapse interval < 12 months 18.4%

0.1 0.0 0

1

2


10 11 12

Figure 3 Univariate analysis of probability of survival from relapse according to disease stage at relapse and interval from SCT to relapse: (a) cytogenetic and chronic phase relapses vs accelerate phase and blast crisis, and (b) SCT-relapse interval 4 vs o12 months.

transplant since molecular monitoring for disease recurrence is now able to identify patients at high risk of cytogenetic or hematological relapse.17–19 Our retrospective study reflects the general practice in the treatment of CML relapse after SCT in the last decade. DLI and a-IFN were the treatments of choice for relapse in cytogenetic or hematological CP and only a few patients received a second SCT as salvage therapy. Most patients in advanced phase relapse received multidrug chemotherapy or palliative care. If the first relapse treatment fails to achieve a cytogenetic or molecular response, patients received a second or even a third type of treatment and finally a significant proportion achieved a second durable remission of the disease. In our experience, 40% of the patients alive in remission had received two or three types of treatment. DLI and a-IFN have both demonstrated their efficacy in the treatment of CML relapse.7–11,20,21 Although the aim of our study was not to assess the efficacy of the

individual therapeutic options, we could not find differences between a-IFN and DLI. Features of both the patient and the disease, not specifically analyzed in our study, could have influenced these results. The best therapy for patients with relapse after SCT remains to be defined, especially with the advent of imatinib as a very active drug in the treatment of CML.22–24 In the present study, only a few patients received imatinib after relapse: four as first-line therapy (alone or in combination with DLI) and 13 as second or third type of treatment. Ten patients had a hematological relapse (seven CP, one AP, and two BC) and seven a cytogenetic relapse. All of them but two responded to imatinib (nine cytogenetic and six molecular responses). In this sense, a retrospective EBMT study has shown the results of treating with imatinib a total of 128 patients relapsing in different phases of the disease (51 CP, 31 AP, and 46 BC).13 A total of 50 patients had failed treatment with DLI prior to imatinib. The complete cytogenetic response was 58% for patients in CP, 48% for AP, and 22% for patients in BC. Complete molecular responses were obtained in 25 patients, of whom 21 were in CP or AP. These results seem to be comparable to those obtained in CP patients and better than those reported in AP patients with DLI as first-line treatment.10,11,13,15 Incidence of severe GvHD and marrow suppression after imatinib was low in this study; however, other authors have recently reported recurrence of GvHD and severe trombocytopenia and granulocytopenia in up to 40% of patients treated with imatinib.14 The efficacy of imatinib must be compared with DLI, which has a response rate of 64–86%, associates severe GvHD in 50% of patients, and marrow aplasia in up to 25% of patients with hematological relapses.8–11 Available data show that the majority of molecular remissions after DLI are durable, and thus the majority of responding patients may prove to be cured.10,25,26 However, more follow-up is needed to Bone Marrow Transplantation


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establish the durability of responses achieved with imatinib and the length of the treatment with this drug once a molecular response is reached. Furthermore, the introduction of imatinib as upfront therapy in newly diagnosed CML patients could have the disadvantages of delay allogeneic SCT and/or to perform SCT for advanced phase disease, both factors that seems to increase the risk of relapse after transplant and to worsen the outcome of relapses. These and other new risk factors may also emerge when patients treated with imatinib previous to SCT will relapse after the procedure. In conclusion, a significant proportion of CML patients that relapse after allogeneic transplantation can regain complete and long-lasting remissions with one or more salvage therapies. Disease stage at relapse and time from transplant to relapse were the main factors influencing overall survival and they should be taken into account when comparing results of different salvage treatments.

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