Relapse Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant

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1 (2004) 34, & 2004 Nature Publishing Group All rights reserved /04 $ Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant M Eapen 1, SA Giralt 2, MM Horowitz 1, JP Klein 1, JE Wagner 3, M-J Zhang 1, MS Tallman 4, DI Marks 5, BM Camitta 6, RE Champlin 2, O Ringde n 7, CN Bredeson 1, R Martino 8, RP Gale 9, MS Cairo 10, MR Litzow 11 and M delima 2 1 International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, WI, USA; 2 MD Anderson Cancer Center, Houston, TX, USA; 3 University of Minnesota, Minneapolis, MN, USA; 4 Northwestern University Medical School, Chicago, IL, USA; 5 Bristol Children s Hospital, Bristol, UK; 6 Medical College of Wisconsin, Milwaukee, WI, USA; 7 Huddinge University Hospital, Huddinge, Sweden; 8 Hospital San Creu I Sant Pau, Barcelona, Spain; 9 Center for Advanced Studies in Leukemia, Los Angeles, CA, USA; 10 Columbia University, New York, NY, USA; and 11 Mayo Clinic Rochester, Rochester, MN, USA Summary: Treatment options for persons with leukemia relapsing after allogeneic transplantation are limited. We analyzed the outcome of 279 patients with acute and chronic leukemia, who relapsed after HLA-identical sibling transplantation and received a second allogeneic transplant. The influence of potential risk factors on treatment-related mortality (TRM), relapse, treatment failure (relapse or death) and overall survival after second transplantation were assessed using proportional-hazards regression. The cumulative incidences (95% confidence interval) of relapse and TRM at 5 years were 42 (36 48)% and 30 (24 36)%, respectively. The 5-year probabilities of both overall and leukemia-free survival were 28 (23 34)%. In multivariate analyses, risks of treatment failure and mortality were lower in younger patients (p20 years) and patients who relapsed after 6 months from first transplantation. Risks of relapse were lower in patients who relapsed after 6 months from first transplantation and in complete remission prior to second transplantation. Risks of relapse were higher after reduced-intensity conditioning regimens. Any potential advantage of using a different matched related donor for a second transplantation is not supported by these data. Although age, disease status and conditioning regimen are important, duration of remission after first transplantation appear to be the most important determinant of outcome. (2004) 34, doi: /sj.bmt Published online 23 August 2004 Keywords: second transplantation; leukemia; duration of remission; matched related donor; reduced-intensity conditioning regimen Correspondence: Dr M Eapen, Statistical Center, International Bone Marrow Transplant Registry, Medical College of Wisconsin, 8701 Watertown Plank Road, PO Box 26509, Milwaukee, WI 53226, USA; meapen@mail.mcw.edu Received 27 January 2004; accepted 2 June 2004 Published online 23 August 2004 Leukemia recurs in 20 70% of persons after allogeneic transplantation, with risk of recurrence depending primarily on the type of leukemia and disease status at transplantation. 1 3 Prognosis of patients who relapse is poor and an optimal salvage therapy has yet to be established. Current treatment options include chemotherapy, donor leukocyte infusions (DLI) and second allogeneic transplantation. Intensive chemotherapeutic regimens can induce remission in some patients with recurrent leukemia, but remission durations are short, and most patients die of uncontrolled leukemia or infectious complications. DLI results in durable clinical and molecular remission in chronic myelogenous leukemia (CML), especially when used for early disease. 4 9 Results of DLI for acute leukemia relapsing after allogeneic transplantation are less encouraging; only 10 20% of patients achieve complete remission (CR) and remissions are usually brief. 6,10,11 Moreover, acute and chronic graft-versus-host disease (GVHD) and infections from marrow aplasia and/or immunosuppressive therapy after DLI are associated with substantial morbidity and mortality. 4,9,11 A new therapy for CML is imatinib mesylate, a tyrosine kinase inhibitor. In the short term, imatinib may be used successfully to induce and maintain remission in CML recurring after allogeneic transplantation. 12 However, follow-up of imatinib-treated patients is short and further studies are required to document durability of remissions. Second allogeneic transplantation may be effective salvage therapy in some patients who relapse after an initial transplant. 1,3,13 21 Thus far, most studies of second transplants for recurrent leukemia are limited by small numbers of patients with heterogeneous prognostic factors. While early relapse after first transplantation and advanced disease status at second transplantation predict poor outcome, data on other factors that may affect outcomes such as conditioning regimen and use of a different donor are few. To better identify risk factors that influence outcome, we studied 279 recipients of second transplants from an HLA-identical sibling donor for leukemia recurring after initial HLA-identical sibling transplantation and

2 722 reported to the International Bone Marrow Transplant Registry (IBMTR). Methods Data collection Data on patients undergoing second allogeneic transplantation were obtained from the Statistical Center of the IBMTR. The IBMTR is a voluntary working group of over 400 transplant teams worldwide that contribute detailed information on their allogeneic transplants to a Statistical Center at the Medical College of Wisconsin. Participating centers are required to register all consecutive transplant recipients. The IBMTR database includes information on 40 45% of allogeneic transplants performed worldwide since Transplant recipients are followed longitudinally. Computerized error checks, physician review of submitted data, and on-site audits of participating centers ensure data quality. Inclusion criteria The study includes patients, with acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) or CML, who received a second allograft from an HLAidentical sibling for recurrent or persistent leukemia after initial HLA-identical sibling transplantation, and transplanted between January 1, 1990 and December 31, In all, 279 patients fulfilled the eligibility criteria (Table 1). Data from the IBMTR suggest that approximately 6% of patients, with recurrent leukemia after a first matched related donor transplant receive a second matched related donor transplant using the same or a different donor. Patients who received DLI for recurrent leukemia after their initial transplant were excluded. Transplant teams reporting to the IBMTR are requested to indicate whether patients received a blood or marrow infusion as a second or subsequent transplant, or DLI. Inconsistencies are resolved by either a data manger or physician at the transplant center. End points The study examined hematologic recovery, acute and chronic GVHD, treatment-related mortality (TRM), relapse, leukemia-free survival (LFS), treatment failure (relapse or death, inverse of LFS) and overall survival after second allogeneic transplantation for recurrent leukemia. The outcome data were compiled from the date of second transplantation to date of last contact or death. Hematopoietic recovery was defined as achieving an absolute neutrophil count (ANC) X500/ml and platelets X20 000/ml. The incidence of grades 2 4acute GVHD was evaluated in all patients; 22,23 chronic GVHD was evaluated in patients surviving 90 days or longer after second transplant. 24 TRM was defined as death in continuous remission; patients were censored at relapse or, for those in clinical remission, at last follow-up. was defined as hematologic recurrence for both acute and chronic Table 1 Characteristics of 279 patients receiving a second HLAidentical sibling transplant for recurrent/persistent disease after their initial HLA-identical sibling transplant Variable 1st transplant N(%) 2nd transplant N(%) Disease AML 125 (45) 125 (45) ALL 72 (26) 72 (26) CML 82 (29) 82 (29) Age (years) p10 51 (18) 40 (14) (20) 56 (20) (23) 64(23) (39) 119 (43) Karnofsky score X90% 229 (83) 154(55) Year, transplant (35) (44) 188 (67) (20) 91 (33) Same donor as 1st transplant 238 (85) Donor recipient sexmatch Male-male 110 (39) 103 (37) Male-female 53 (19) 50 (18) Female-male 65 (23) 72 (26) Female-female 51 (19) 54(19) Time from 1st transplant to relapse, median (range), months Time from relapse to 2nd transplant, median (range), months 14(1 155) 4 (o1 48) Disease status at transplant Remission 212 (76) 144 (52) 67 (24) 135 (48) Graft type Bone marrow 264(95) 220 (79) Peripheral blood 12 (4) 59 (21) Umbilical cord blood 3 (1) Myeloablative conditioning regimen Cy/TBI7other 134(48) 63 (23) TBI7other 16 (6) 27 (10) Busulfan/Cy7other 127 (46) 114 (41) Melphalan7other 2 (o1) 6 (2) Cy/other 4(1) Busulfan/other 20 (7) Reduced intensity conditioning regimen a TBI regimen 1 (o1) Non-TBI regimen 44 (16) GVHD prophylaxis None 38 (14) CSA7other 59 (21) 96 (34) MTX7other 21 (8) 29 (10) CSA/MTX7other 148 (53) 99 (35) T depletion7other 41 (15) 3 (1) Other 4(1) 4(1) Missing 6 (2) 10 (4) Follow-up of survivors, median (range), months 93 (6 147) AML¼ acute myeloid leukemia; ALL ¼ acute lymphoid leukemia; CML ¼ chronic myeloid leukemia; TBI ¼ total body irradiation; CSA ¼ cyclosporine; MTX ¼ methotrexate; Cy ¼ cyclophosphamide; Ara-C ¼ cytosine arabinoside. a Reduced intensity conditioning regimens were defined as: any fludarabinecontaining regimen; TBIo400 cgy7other agents; melphalan p150mg/ m 2 7Ara-C/etoposide; cyclophosphamide7ara-c; busulfan p12 mg/ kg7ara-c/etoposide; high-dose Ara-C7etoposide.

3 leukemia; patients who never achieved remission after second transplantation were considered to have had a recurrence at day 1. LFS was defined as survival in continuous CR; relapse or death were considered events; and patients surviving in continuous CR were censored at last follow-up. Statistical analysis Probabilities of LFS and overall survival were calculated using the Kaplan Meier estimator. 25 Cumulative incidence rates (the chance a patient will have experienced a particular competing risk prior to time t, and where death without an event is the competing risk) were calculated using standard techniques for hematopoietic recovery, acute and chronic GVHD, TRM and relapse. 25 The standard error of the survivor function by Greenwood formula was used to calculate the 95% confidence intervals (CI). 25 Potential prognostic factors for TRM, relapse, treatment failure and overall mortality were evaluated in multivariate analyses using Cox proportional-hazards regression. 26 Multivariate models were built using a stepwise forward selection with a significance level of Variables considered in multivariate analyses are shown in Table 2. Whenever categories of variables initially classified into Table 2 models Variables tested in Cox proportional-hazards regression Patient-related variables Age at 2nd transplant a : p10 vs years vs vs 430 years* Gender: male vs female* Disease-related variables Type of leukemia: ALL vs AML vs CML* Disease status at 2nd transplant: relapse/persistent disease vs remission* Time from 1st transplant to relapse b : p6 vs vs 412 months* Time from relapse to 2nd transplant: p3 months vs 43 months* Transplant-related variables 1st transplant Disease status at 1st transplant: relapse/persistent disease vs remission* Conditioning regimen: non-tbi regimen vs TBI* GVHD prophylaxis: T depletion vs T-replete allograft* Grades 2 4acute GVHD after 1st transplant Chronic GVHD after 1st transplant 2nd transplant Year of transplant: vs * Graft type: peripheral blood vs bone marrow* Donor: different sibling other vs same donor as 1st transplant* Donor recipient sex match: other vs female-male* Conditioning regimen: TBI regimen vs reduced intensity vs non-tbi regimen* GVHD prophylaxis: CSA7MTX7steroids vs other vs none* *Reference group. a Age at 2nd transplant: there were no differences between age groups p10 and years, and and 430 years. Therefore, the final model was tested as 420 years vs p20 years*. b Time from 1st transplant to relapse: there were no differences between and 412 months. Therefore, the final model was tested as p6 vs 46 months*. more than two categories showed no statistically significant differences between categories, categories were collapsed to create the fewest possible number groups (such as: age and duration of remission after first transplant). In each model, the assumption of proportional hazards was tested for each variable using a time-dependent covariate. First-order interactions between variables were examined by fitting a proportional-hazards model and examining interaction between variables. Associations between GVHD and leukemia recurrence after transplantation were tested by modeling acute and chronic GVHD as time-dependent covariates with other significant variables in the final multivariate model for relapse. All multivariate models were examined for center effects by using random effects or frailty model; 27 there was no evidence of confounding by center effects. Completeness of follow-up was assessed using a C statistic, which gives a measure of the proportion of all potential follow-up information available for this study. 28 All P-values are two-sided. All analyses were carried out using PROC PHREG in SAS version 8.0 (SAS Institute Inc., Cary, NC, USA). Results Patient and transplant characteristics Patient, disease and transplant characteristics at first and second transplantation are presented in Table 1. All patients received allografts from HLA-identical sibling donors; 85% received allografts from the same donor for both transplants. Graft type, conditioning regimen and GVHD prophylaxis were determined by transplant teams. In all, 90% of second transplants for recurrent CML were between 1990 and Bone marrow was the most common graft type. No patient received an irradiation containing conditioning regimen for both transplants, and 16% received a reduced-intensity conditioning regimen for their second transplant. The median follow-up of survivors is 93 (range 6 147) months and the completeness of followup is 90%. 27 A total of 90% of survivors were followed for at least 2 years after second transplantation. Hematopoietic recovery Most patients achieved hematopoietic recovery. The median times to neutrophil and platelet recovery were 16 (range, 6 82) days and 23 (8 364) days, respectively. The cumulative incidences (95% CI) of achieving ANC X500/ml at day 100 and platelets X20 000/ml at 1 year were 86 (77 92)% and 83 (72 90)%, respectively. Acute and chronic GVHD The cumulative incidence of grade 2 4acute GVHD at day 100 was 29 (24 35)%. The cumulative incidences of chronic GVHD at 1 and 5 years were 39 (31 46)% and 41 (33 48)%, respectively. T-cell depletion for first transplantation or not having received GVHD prophylaxis for the second was not associated with outcomes after second transplantation. To further examine the association, if any, 723

4 724 with GVHD prophylaxis at second transplantation and outcome, we created four categories: same donor, same GVHD prophylaxis for both transplants, same donor, different GVHD prophylaxis for both transplants, different donor, same GVHD prophylaxis for both transplants and different donor, different GVHD prophylaxis for both transplants. During model building, this did not attain a significance level of Nevertheless, this was forced into the final model for TRM, relapse, treatment failure and overall survival, and we did not observe an association. Among patients who did not develop acute GVHD after first transplantation, rates of acute GVHD after second transplantation with the same or a different donor were 29% and 26%, respectively. In contrast, patients who received allografts from the same donor for both transplants and developed grade 2 4acute GVHD after their first transplant were more likely to develop grade 2 4acute GVHD after their second, relative risk (RR) 1.74, 95% CI , P ¼ A similar trend was not observed among patients who developed acute GVHD after first transplant, but received the graft from a different donor for the second transplant. Chronic GVHD was more likely after second transplant in patients who received their allograft from a different donor rather than from the same donor for both transplants (61 vs 37%, P ¼ 0.03), but this did not translate into a survival advantage (39 vs 28%, P ¼ 0.2). Treatment-related mortality Risks of TRM were higher in patients older than 20 years of age and in those who relapsed p6 months after their first transplant (Table 3). The cumulative incidences of TRM at 1 and 5 years were 26 (21 31)% and 30 (24 36)%, respectively (Figure 1). The 1-year cumulative incidence of Table 3 Factors associated with outcomes after second transplantation Variable N RR (95% CI) P-value TRM Age at 2nd HSCT (years) p ( ) o p ( ) p ( ) o Disease status at 2nd HSCT Remission /persistent disease ( ) o Conditioning regimen at 2nd HSCT a Non-TBI myeloablative regimen TBI myeloablative regimen ( ) 0.42 Reduced intensity regimen ( ) 0.01 Treatment failure (inverse of LFS) Age at 2nd HSCT (years) p ( ) p ( ) o Disease status at 2nd HSCT Remission /persistent disease ( ) 0.03 Overall mortality Age at 2nd HSCT (years) p ( ) o p ( ) o a Reduced intensity vs TBI myeloablative regimen*: 1.58 ( ) P ¼ *Reference group.

5 Cumulative incidence, % TRM in patients with neither of these risk factors (n ¼ 71) was 20 (12 30)%; in patients with both risk factors (n ¼ 36), the cumulative incidence was 25 (14 38)% The cumulative incidences of relapse at 1 and 5 years were 36 (31 42)% and 42 (36 48)%, respectively (Figure 1). Risk of relapse was higher in patients with a short (p6 months) remission after first transplant, those who were not in CR at second transplant and those who received reducedintensity conditioning (Table 3). Grade 2 4acute GVHD after second transplant was associated with lower risk of relapse, RR 0.50, 95% CI , P ¼ Risk of relapse was similar in patients with and without chronic GVHD after second transplant. Treatment failure Years TRM Figure 1 Cumulative incidence of relapse and TRM after second transplantation. Probability, % A B 0.6 C D 0.4 E F 0.2 G H Years Figure 2 Probability of LFS after second transplantation. (A) Age p20 years, duration of remission 46 months and in CR; (B) age p20 years, duration of remission 46 months and not in CR; (C) age 420 years, duration of remission 46 months and in CR; (D) age 420 years, duration of remission 46 months and not in CR; (E) age p20 years, duration of remission p6 months and in CR; (F) age p20 years, duration of remission p6 months and not in CR; (G) age 420 years, duration of remission p6 months and in CR; and (H) age 420 years, duration of remission p6 months and not in CR. Probabilities of LFS at 1 and 5 years were 38 (32 43)% and 28 (23 34)%, respectively. Risk of treatment failure was higher in patients older than 20 years of age, in those who relapsed p6 months after their first transplant and in those not in CR at second transplantation (Table 3). Among Probability, % B 0.2 C D patients with none of these risk factors (n ¼ 71), the 5-year probability of LFS was 49 (36 60)%; among those with all these risk factors (n ¼ 36), the probability was 3 ( )% (Figure 2). Overall survival Probabilities of overall survival at 1 and 5 years were 41 (35 46)% and 28 (23 34)%, respectively. Risk of mortality was higher in patients older than 20 years of age and in those who relapsed p6 months after their first transplant (Table 3). Among patients with neither of these risk factors (n ¼ 71), the 5-year probability of overall survival was 51 (38 62)%; among those with both risk factors (n ¼ 36), the probability was 3 ( )% (Figure 3). Disease status at transplantation was not associated with overall mortality, RR 1.26, 95% CI , P ¼ In total, 202 patients (72%) died. Recurrent leukemia (58%) was the most frequently reported primary cause of death. Other reported causes included GVHD (11%), interstitial pneumonitis (12%), infections (9%), organ failure (5%), second malignant neoplasm (1%) and other causes (4%). The median (range) time from second transplantation to death was 4(o1 100) months. Discussion Years Figure 3 Probability of overall survival after second transplantation. (A) Age p20 years, duration of remission 46 months; (B) age 420 years, duration of remission 46 months; (C) age p20 years, duration of remission p6 months; and (D) age 420 years, duration of remission p6 months. A second allogeneic transplant for leukemia recurring after first transplant may be a reasonable treatment option in selected patients. However, identification of factors influencing relapse and mortality after second transplantation and determination of patient groups who best respond to this therapy have proven difficult. Using data from the IBMTR, Mrsic et al 1 reported outcomes in 114recipients of second HLA-identical sibling transplants between 1978 and In their study, relapse occurring later than 6 months after first transplant, diagnosis of CML and CR at second transplant were associated with a better outcome. The primary objective of the current study was to identify potential risk factors in a more contemporary period. We found length of remission after first transplant, and age, disease status and conditioning regimen at second trans- A 725

6 726 plant to be important in determining outcomes after second transplant. Although acute GVHD after second transplant correlated with a lower risk of relapse, we found no evidence to support the use of a different matched related donor to increase the likelihood of developing GVHD after second transplantation. Our data, as well as other reports, indicate that length of remission after first transplantation is probably the most important variable predicting outcome after second transplant. 1,3,15,17 21, treatment failure and mortality are higher in patients with early relapse. We defined early relapse as occurring within 6 months after first transplant. Interestingly, we observed similar outcomes for patients who relapsed 7 12 months and those who relapsed later after their first transplant. This contrasts with other recent reports suggesting better outcomes in patients relapsing in the first year after transplantation. 3,20,21 Similar to other reports, we did not observe a correlation between interval from relapse to second transplant and treatment failure or mortality. 1,3,17,20 As expected, patients with active leukemia at transplant were also less likely to do well, similar to other reports. 1,3,19,20 Age correlated with TRM, treatment failure and overall mortality, probably the result of better tolerance of therapy in younger patients. Factors generally accepted as predicting outcomes after first transplant, such as duration of pretransplant remission for acute leukemia, interval from diagnosis to first transplant for chronic leukemia, and disease status at first transplant, did not correlate with the outcome after second transplant. In addition, the specific conditioning or GVHD prophylaxis regimen for first transplant did not seem to predict the outcome of the second transplantation. In contrast to some reports, outcomes were not different among the three disease groups, ALL, AML and CML. The 3-year probabilities of LFS for AML, ALL and CML were 27 (19 35)%, 30 (20 42)% and 32 (23 43)%, respectively. Corresponding probabilities of overall survival were 27 (19 35)%, 30 (20 42)% and 33 (23 44)%. Although the variable for type of leukemia (AML vs ALL vs CML) did not attain a significance level of 0.05, this variable was forced into all final models and the outcomes were unchanged. We defined leukemia relapse as hematological recurrence for both acute and chronic leukemia, and this may explain why we did not observe differences in outcome by type of leukemia. We do not have data on cytogenetics or chimerism, chemosensitive vs refractory disease, and other hematological markers such as the percent of circulating blasts, and platelet count at relapse after first transplantation. While these factors may be of prognostic significance, we were unable to examine their prognostic significance in this data set and acknowledge this as one of the limitations of a registrybased study. Most transplant strategies rely heavily on maximally tolerated doses of chemotherapy, with or without radiation, to eradicate cancer, and allografts to rescue patients from therapy-induced marrow aplasia as well as to provide immune-mediated effects. Some reports suggest that conditioning regimens with total body irradiation (TBI) may lower mortality in patients with acute leukemia after second transplantation. 3 We did not observe this. Only a third of patients in this study received a TBI-containing regimen and AML was the most common disease in this group. Most patients with ALL and CML received a TBIcontaining regimen for their first transplant. More recently, reduced-intensity conditioning regimens and postgrafting immunosuppression to control graft rejection and GVHD have been used to reduce regimen-related toxicities while preserving graft-versus-leukemia (GVL) effects. 29,30 We found higher rates of relapse after reduced-intensity conditioning. This was independent of the duration of remission after first transplant and disease status at second transplant, suggesting that dose intensity may be important in this setting. These findings should be interpreted with caution due to lack of homogeneity of reduced intensity conditioning regimens, as well as probable biases in patient selection for this relatively new form of therapy. We found no evidence supporting the use of a different HLA-identical donor for a subsequent transplant. Risks of relapse and mortality were similar whether or not a different donor was used. Using a different matched related donor, when available, for a subsequent transplant to increase the likelihood of GVHD and subsequent GVL effect is not supported by these data. As only 15% of the study population received their second allograft from a different HLA-identical sibling donor, small numbers may have limited our ability to detect differences. While some studies in adults report survival advantages after peripheral blood stem cell (PBSC) infusion for advanced leukemia, 31,32 others 3 report lower risks of relapse using bone marrow for second transplant. We did not observe a correlation between graft source and risks of relapse or mortality. However, as only 21% of the study cohort received PBSC grafts, small numbers may have limited our ability to detect an effect. DLI, and more recently, imatinib mesylate have been used successfully to maintain durable clinical and molecular remission in CML. 4 9,12 This study population includes patients with CML in hematologic relapse. Although current standard of care for recurrent CML are DLI and/or imatinib mesylate, for those who fail this therapy, a second transplant may be an option. As such, the data presented here may serve as a reference when counseling these patients who have failed DLI and/or imatinib mesylate. A retrospective report such as ours has limitations such as selection bias for transplantation, choice of conditioning regimen and our inability to adjust for unknown or unmeasured factors that may affect the outcome after transplantation. The data suggest, with a median follow-up of over 7 years, that second allogeneic transplantation produces sustained remission in a proportion of patients. Although disease status, age and conditioning regimen are important, duration of remission after first transplant appears to be the most important determinant of outcome. There seems little point in subjecting patients with posttransplant remission durations of p6 months to a second aggressive procedure. Use of a different matched related donor to improve outcomes after a subsequent transplant is not supported by these data. Further controlled studies are required to define the role of reduced vs standard intensity conditioning regimens in this setting.

7 Acknowledgements This work was supported by a Clinical Research Career Development Award from the American Society of Clinical Oncology (ME), Public Health Service Grant U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, the National Heart, Lung and Blood Institute and the Cancer Center, Medical College of Wisconsin. References 1 Mrsic M, Horowitz MM, Atkinson K et al. Second HLAidentical sibling transplants for leukemia recurrence. Bone Marrow Transplant 1992; 9: Kumar L. Management of relapse after allogeneic bone marrow transplantation. J Clin Oncol 1994; 7: Bosi A, Laszlo D, Labopin M et al. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European cooperative group for blood and marrow transplantation. J Clin Oncol 2001; 9: Mackinnon S, Papadopoulos EB, Carabasi MH et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-host disease. Blood 1995; 86: Bacigalupo A, Soracco M, Vassallo F et al. Donor lymphocyte infusion (DLI) in patients with chronic myeloid leukemia following allogeneic bone marrow transplantation. Bone Marrow Transplant 1995; 19: Collins RH, Shpilberg O, Drobyski WR et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: Dazzi F, Szydlo R, Goldman J et al. Donor lymphocyte infusions for relapse of chronic myeloid leukemia after allogeneic stem cell transplant: Where we now stand. Exp Haematol 1999; 27: Dazzi F, Szydlo RM, Cross NCP et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000; 96: Porter DL, Collins RH, Hardy C et al. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000; 95: Carlens S, Remberger M, Ascham J, Ringde n O. The role of disease stage in the response to donor lymphocyte infusions as treatment for leukemic relapse. Biol Blood Marrow Transplant 2001; 7: Levine JE, Braun T, Penza SL et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplant. J Clin Oncol 2000; 20: Kantarjian HM, O Brien S, Cortes JE et al. Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 2000; 100: Barrett AJ, Locatelli F, Treleaven JG et al. Second transplants for leukemic relapse after bone marrow transplantation: high early mortality but favorable effect of chronic GVHD on continued remission. Br J Haematol 1991; 79: Wagner JE, Vogelsang GB, Zehnbauer BA et al. of leukemia after bone marrow transplantation: effect of second myeloabalative therapy. Bone Marrow Transplant 1992; 9: Radich JP, Sanders JE, Buckner CD et al. Second allogeneic transplantation for patients with recurrent leukemia after initial transplantation with total body irradiation-containing regimen. J Clin Oncol 1993; 11: Martino R, Badell I, Brunet S et al. Second bone marrow transplantation for leukemia in untreated relapse. Bone Marrow Transplant 1994; 14: Chaing K-Y, Weisdorf DJ, Davies SM et al. Outcome of second bone marrow transplantation following a uniform conditioning regimen as therapy for malignant relapse. Bone Marrow Transplant 1996; 17: Bosi A, Bacci S, Miniero R et al. Second allogeneic bone marrow transplantation in acute leukemia: a multicenter study from the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO). Leukemia 1997; 11: Kishi K, Takahashi S, Gondo H et al. Second allogeneic bone marrow transplantation for post-transplant leukemia relapse: results of a survey of 66 cases in 24Japanese institutes. Bone Marrow Transplant 1997; 19: Michallet M, Tanguy ML, Socie G et al. Second allogeneic heamtopoietic transplantation in relapsed acute and chronic leukemias for patients who underwent a first allogeneic bone marrow transplantation: a survey of the Societe Francaise de Greffe de Moelle (SFGM). Br J Haematol 2000; 108: Tomonari A, Iseki T, Ooi J et al. Second allogeneic hematopoietic stem cell transplantation for leukemia relapse after first allogeneic transplantation: outcome of 16 patients in a single institution. Int J Hematol 2002; 75: Glucksberg H, Storb R, Fefer A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-identical sibling donors. Transplantation 1974; 18: Przepiorka D, Weisdorf D, Martin P et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: Atkinson K, Horowitz MM, Gale RP et al. Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood 1990; 75: Klein JP, Moeschberger ML. Survival Analysis: Techniques of Censored and Truncated Data. Springer-Verlag: New York, NY, Cox DR. Regression models and life tables. J R Stat Soc Ser B 1972; 34: Andersen PK, Klein JP, Zhang M-J. Testing for center effects in multi-center survival studies: a Monte Carlo comparison of fixed and random effects tests. Stat Med 1999; 18: Clark TG, Altman DG, De Stavola BL. Quantification of the completeness of follow up. Lancet 2001; 359: Giralt S, Estey E, Albitar et al. Engraftment of allogeneic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89: Pawson R, Potter MN, Theocharous P et al. Treatment of relapse after allogeneic bone marrow transplantation with reduced intensity conditioning (FLAG7Ida) and second allogeneic stem cell transplant. Br J Haematol 2001; 115: Champlin RE, Schmitz N, Horowitz MM et al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. Blood 2000; 95: Bensinger WI, Martin PJ, Storer B et al. Transplantation of bone marrow as compared with peripheral blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001; 344: