Originally published as JCO Early Release 10.1200/JCO.2005.03.1765 on December 12 2005

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Treatment for Acute Myelogenous Leukemia by Low-Dose, Total-Body, Irradiation-Based Conditioning and Hematopoietic Cell Transplantation From Related and Unrelated Donors

From the University of Leipzig, Leipzig, Germany; Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, WA; Stanford University, Palo Alto, CA; Bone Marrow Transplant Unit, Medical University of Vienna, Austria; Hopital Henri Mondor, Creteil, Hotel Dieu, Paris, France; University Hospital, Basel, Switzerland; University of Colorado, Denver, CO; Seattle Veterans Administration Medical Center, Seattle, WA; Baylor University, Dallas, TX; University of Torimo, Torimo, Italy; Oregon Health & Science University, Portland, OR; and University of Utah, Salt Lake City, UT

Address reprint requests to Dietger Niederwieser, MD, Division of Hematology and Oncology, University of Leipzig, Johannissallee 32A, D-4103 Leipzig, Germany; e-mail: dietger{at}medizin.uni-leipzig.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix: Participating Centers Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose The use of low-dose, irradiation-based preparative regimens have allowed the extension of allografting to older and medically infirm patients. The study reported here assessed outcomes for patients with acute myeloid leukemia (AML) in different stages of their disease, who were not considered candidates for conventional hematopoietic cell transplantation (HCT) because of age and/or other known risk factors and were given minimal conditioning followed by HCT from related or unrelated donors.

Patients and Methods The present study included 122 patients with AML, who were conditioned with 2 Gy total-body irradiation (TBI) on day 0 with or without preceding fludarabine (30 mg/m²/d from days –4 to –2), and given postgrafting cyclosporine at 6.25 mg/kg twice daily from day –3 and mycophenolate mofetil at 15 mg/kg twice daily from day 0.

Results Durable engraftment was observed in 95% of the patients. Cumulative incidences of acute graft-versus-host disease grades 2 to 4 at 6 months were 35% after related and 42% after unrelated HCT, respectively. With a median follow-up of 44 months (range, 26 to 79 months), 51 patients were alive, of whom 48 were in complete remission (CR). Cumulative nonrelapse mortalities were 10% and 22%, and cumulative mortalities from disease progression were 47% and 33% at 2 years for related and unrelated recipients, respectively. Overall, 2-year survival was 48%, and disease-free survival was 44%. Patients receiving transplantation in CR1 had 2-year overall survivals of 44% after related and 63% after unrelated HCT, respectively.

Conclusion We conclude that HCT from related and unrelated donors after low-dose TBI is a promising treatment for elderly patients with AML.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix: Participating Centers Authors' Disclosures of... Author Contributions REFERENCES

 
Complete remissions (CR) can be achieved with induction chemotherapy in approximately 65% of adults with de novo acute myeloid leukemia (AML).^1-6 Postremission therapies result in disease-free survivals (DFS) of 10% to 35% at 5 years. Outcomes are largely determined by biologic risk factors such as specific genetic mutations, cytogenetic abnormalities, and older patient age.^7-10 The vast majority of older patients with AML have more adverse prognostic features than younger patients and, despite reaching initial CR, most older patients relapse within 2 years of diagnosis and die within 3 years.^{1,2,8,9,11-14} No chemotherapy regimen provides durable remission or long-term survival in more than a small percentage of patients with AML in CR2 or beyond.¹²

Results can be improved by high-dose postremission therapy with autologous hematopoietic cell transplantation (HCT) or by allogeneic HCT, which has the highest potential of curing patients with AML. Given the toxicity of the treatment, however, allogeneic HCT is limited to younger patients without comorbidities.

During the last years, reduced and minimal intensity conditioning were developed with the aim of using the curative potential of allogeneic HCT in elderly and medically infirm patients as well.^15-20 Initial data from patients with various hematologic malignancies have demonstrated the feasibility of allogeneic HCT after conditioning with a minimal-intensity regimen consisting of 2 Gy total-body irradiation (TBI) with or without fludarabine and postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP).^19-22 The study reported here assessed outcomes for patients with AML in different stages of their disease, who were not considered candidates for conventional high-dose HCT and were given minimal conditioning followed by HCT from related or unrelated donors.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients with AML received transplantation at eight United States and five European centers using the same protocol approved by the Institutional Review Boards at each of the participating sites. Patients were eligible for unrelated HCT if they were more than 50 years old and for related HCT if they were more than 55 years old. Younger patients were included if they had comorbid conditions (eg, aspergillosis) that excluded them from conventional allogeneic HCT. Reasons for performing HCT in CR1 were persistent cytogenetic or molecular evidence of disease, high-risk cytogenetics at diagnosis, age more than 60 years, and secondary AML in younger patients with comorbidities. No exclusions were made for renal insufficiency or active bacterial or fungal infections.

HLA Typing and Matching
All related and 61 of 64 unrelated donor-recipient pairs were selected on the basis of serologic matching for human leukocyte antigen (HLA) class I and molecular matching for HLA-DRB1 and -DQ1. Three unrelated pairs had one HLA-A or HLA-B antigen mismatches. In addition, retrospective allele level typing was performed in the majority of donor-recipient pairs for HLA-A, -B, -C, -DQB1, and -DPB1 alleles using direct automated fluorescent methods, as described.^23,24 Overall, one or more antigen and/or allele level mismatches were recognized in 22 of the 64 unrelated donor-recipient pairs. Mismatches were present in 19 and 21 pairs by rejection and by graft-versus-host disease (GvHD) vector, respectively.

Patient Characteristics
Between July 1998 and December 31, 2002, 122 patients were enrolled in the study. The results of 18 previously reported patients²² have been updated, and data on 104 additional patients have been included. Their characteristics are presented in Table 1. Eighteen patients had secondary AML, 51 patients were in CR1, 39 patients were in CR2, and 32 patients had more advanced stages of AML. The distributions of cytogenetic risks among related and unrelated recipients were comparable, but 55% of related compared with 30% of unrelated recipients were in CR1. Median time from last chemotherapy to HCT was 76 days (range, 7 to 491 days) with no difference between related and unrelated recipients.

Transplant Procedure
All patients were conditioned with a single fraction of 2 Gy TBI delivered at 0.07 to 0.20 Gy/min from linear accelerators or opposing dual cobalt 60 sources on day 0. In addition, all unrelated and 39 related recipients (all receiving transplantation after October 2000) were given fludarabine, 30 mg/m²/d, from days –4 to –2. Granulocyte colony-stimulating factor mobilization and harvest of peripheral blood mononuclear cells (G-PBMC), marrow harvest procedures, infusion of donor hematopoietic cells, immunosuppressive therapy, and antimicrobial prophylaxis were performed, as previously reported.^19-22 Graft characteristics are presented in Table 2. Toxicities were determined using the National Cancer Institute Common Toxicity Criteria, Version 2.0. Percentages of donor chimerism were assessed by fluorescent in situ hybridization for X and Y chromosomes and/or by polymerase chain reaction-based amplification of variable number tandem repeat sequences after flow cytometry sorting, as previously described.²⁰ The local investigators performed GvHD grading using standard criteria.^25,26 In selected patients, residual disease was measured using molecular studies.²⁷

Statistical Analyses
Data were analyzed as of March 1, 2005. Patients without evidence of relapse and progression were considered to have died of nonrelapse causes. Survival and DFS were estimated by the Kaplan-Meier method. Risk factors were analyzed using proportional hazards regression models, treating death before acute GvHD, rejection, and relapse as competing events. Rejection was treated as a competing event for acute GvHD and as a time-dependent covariate for death and relapse. The factors considered in the univariate analyses were disease risk, diagnosis, HLA mismatches, and rejection. The multivariate models were constructed in stepwise fashion. All P values were derived from likelihood ratio statistics and were 2-sided.

	RESULTS

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Peripheral-Blood Cell Changes, Allogeneic Engraftment, and Graft Rejection
The hematologic toxicities after HCT were moderate (Table 2). Twenty-two related patients (38%) and 11 unrelated patients (17%) did not have absolute neutrophil counts (ANC) less than 500/µL. Platelet transfusions were not required in 71% of related and 42% of unrelated recipients. RBC transfusions were not given to 50% of related and 16% of unrelated recipients (Table 2).

One of the 122 patients died on day 8, too early to be assessed for engraftment. Among the remaining 121 patients, 115 patients (95%) had sustained engraftment. The median percentages of donor chimerism levels among marrow mononuclear cells, peripheral blood granulocytes (CD33⁺ or CD15⁺-cells), and T-cells (CD3⁺-cells) over the first 180 days were consistent with rapid engraftment (Fig 1). Six patients (5%) rejected their grafts; three of the four unrelated recipients had received marrow grafts and one G-PBMC with a low CD34⁺ cell count (0.76 x 10⁶/kg); and both related recipients had received TBI alone as conditioning. Graft rejection was accompanied by prolonged neutropenia and thrombocytopenia with eventual autologous recovery in four patients, while two patients received a successful second HCT from different unrelated donors. The use of marrow instead of G-PBMC, low CD34+, and low CD3+ cell doses were risk factors for rejection in univariate analysis.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Percent donor chimerism after HCT. Median percentages of NK cells (), donor peripheral blood CD33+, CD15+ cells (granulocytes; 0), and CD3+ cells (T-lymphocytes; •) are shown for the first 180 days from transplant. HCT, hematopoietic cell transplantation; NK, natural killer.

Fungal pneumonias were diagnosed in 6.9% of related recipients and 7.8% of unrelated recipients. Two unrelated recipients died from fungal pneumonias before day 100.

GvHD
Forty-eight patients (40.0%) developed acute GvHD, which was grade 2 in 34 patients, grade 3 in eight patients, and grade 4 in six patients (Table 2 and Fig 2). All six patients with grade 4 and one patient with grade 3 acute GvHD died.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Cumulative probabilities of grades 2, 3, and 4 acute graft-versus-host disease (GvHD).

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Cumulative incidence of extensive chronic graft-versus-host disease (GvHD).

Patients with sustained engraftment. Among the 115 patients with durable engraftment, 48 patients relapsed, of whom, 45 patients have died of disease progression, while two patients are alive in CR with complete donor chimerism following withdrawal of immunosuppression, and one patient is alive in CR after a second transplant. Specifically, 19 of the 47 patients with CR1 (40%), 14 of 38 patients with CR2 (37%), and 15 of 32 patients beyond CR2 (47%) relapsed.

Twenty-four of the 32 patients beyond CR2 had partial remission (PR)/refractory AML, of whom, 18 patients (eight PR and 10 refractory) underwent unrelated and six patients (one PR and five refractory) underwent related HCT. Nine of the 18 unrelated recipients and three of the six related recipients achieved CR, however, none of the patients with more than 15% blasts at transplant became long-term survivors.

CBFβ-MYH11 nested reverse transcriptase polymerase chain reaction done in two patients with CR1 became negative on days 42 and 57 and has remained negative for more than 800 days after HCT.

Donor Lymphocyte Infusions for Relapse, Mixed Chimerism, and Rejection
DLIs were given for relapse/persistent disease to 14 patients, of whom, 12 patients had received related grafts, and two patients received unrelated grafts. Thirteen of the 14 patients died from relapse between 1 and 595 days after DLI. One patient is alive in remission.

DLIs were given for low-level donor chimerism to seven patients. One patient died of liver GvHD, two patients relapsed, and four patients are alive in remission. DLIs were unsuccessfully administered to two patients with pending graft rejection.

Survival and Causes of Death
With a median follow-up of 44 months (range, 26-79 months), 51 of the 122 patients were alive. Of these, 48 patients were in CR, one patient had developed myelodysplastic syndrome after graft rejection, and two patients were in CR after a second HCT. Specifically, 25 of the 58 related recipients and 26 of the 64 unrelated recipients were alive. The probabilities of overall and DFSs at 2 years were 48% and 44%, respectively (Table 2), with no statistically significant differences between related and unrelated as well as younger (< 60 years) and older (> 60 years) recipients. For patients receiving transplantation in CR1, overall survival was 51% at 2 years. Results were similar for patients receiving transplantation in CR2 with overall 2-year survivals of 61%, while overall 2-year survival in patients with AML beyond CR2 was 28% (Table 2 and Fig 4). Factors influencing survival in a multivariate analysis were disease stage at HCT, HLA mismatch, and cytogenetic risk (Table 4).

View larger version (27K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Overall survival, relapse, and nonrelapse mortality in relation to the disease status at HCT and donor relationship. Patients were in (A and B) CR1 (n = 51), (C and D) CR2 (n = 39), and (E and F) beyond CR2 (n = 32) before transplant and received either related (A, C1; C, CR2; and E, beyond CR2) or unrelated (B, CR1; D, CR2; and F, beyond CR2) grafts. HCT, hematopoietic cell transplantation, CR, complete remission.

	DISCUSSION

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The current analysis extended previous reports on the use of these regimens in patients with various hematologic malignancies.^19-22 The multicenter study included 122 patients with AML, who, in all but five cases were ineligible for conventional HCT because of age and/or medical contraindications. More than half of the patients (58%) were in CR2, 15% had secondary AML, and 17% had adverse cytogenetic risk factors.

In agreement with the earlier observations, HCT was well-tolerated and resulted in a > 95% rate of sustained engraftment. The hematopoietic toxicities of the HCT regimen were moderate with ANCs in approximately 30% of patients not declining below 500/µL, more than half of the patients not requiring platelet transfusions, and approximately 30% not requiring RBC transfusions. Unrelated recipients had slower engraftment, lower ANC and platelet nadirs, and higher transfusion requirements than related recipients. In part, this might explain the three times higher bacterial and twice higher viral infection rates among unrelated compared with related recipients, though fungal infection incidences were comparable. In part, differences in infection rates might be related to greater incidence of failed preceding autologous HCT, more advanced disease stages, and greater degrees of HLA-disparities with their donors among unrelated recipients.

While engraftment rates with these regimens have been high, two complications have limited the eventual success of the procedure, relapse and nonrelapse mortalities. The regimens have relied virtually entirely on graft-versus-leukemia effects for both maintaining remissions in patients receiving transplantation without and achieving remissions in those receiving transplantation with measurable disease. While impressive, graft-versus-leukemia effects were not universally effective. The percentages of patients who remained disease-free were higher when grafts were carried out in first or second CR compared with more advanced disease stages. These findings emphasized that allogeneic HCT with reduced intensity conditioning should be considered earlier in patients with AML. In fact, cure rates with continued chemotherapy in patients > 55 years of age in CR1 have been reported to be no better than 10% to 15%.¹³ This compared with 44% and 63% continued remission, respectively, in current CR1 patients given related or unrelated grafts. As for patients in CR2 or in relapse, there have been no survivors with chemotherapy alone.¹² In contrast, relapse rates for CR2 patients given related or unrelated HCT in the current study ranged from 34% to 38% and those for more advanced patients from 63% to 42% for related and unrelated recipients, respectively. As a result, 68% related patients and 57% unrelated patients in second CR and 25% related patients and 29% unrelated patients beyond second CR have become long-term survivors, respectively. Reductions of the relapse rates after HCT, following reduced intensity conditioning, might eventually be achieved with a better understanding of the polymorphic minor histocompatibility antigens and/or by adding targeted therapy to the conditioning regimen.

Cumulative nonrelapse mortalities at 2 years were 10% after related and 22% after unrelated transplantation (P = .03). The difference between the two groups of recipients might be caused, in part, by greater comorbidity scores and, in part, by greater degrees of histoincompatibility among unrelated donor-recipient pairs. GvHD has remained a major cause of morbidity and mortality after reduced-intensity conditioning HCT. Complications from acute GvHD have resulted in the death of 6% of all patients, and another 3% have died from chronic GvHD. Nevertheless, GvHD rates among patients with reduced conditioning tended to be lower than among those given ablative conditioning, even though patients with reduced conditioning were older.^28,29 This difference might, in part, be explained by reduced tissue damage from less intense conditioning regimens, initial mixed donor/host chimerism, lack of cytokine storm, and potent postgrafting immunosuppression with CSP and MMF. The incidences of acute GvHD among related and unrelated recipients were not significantly different, despite the many partially HLA-mismatched unrelated donor-recipient pairs; perhaps, this was a consequence of the more prolonged MMF administration in unrelated recipients.

Comparable rates of acute GvHD have been reported by Giralt et al¹⁶ in related and unrelated recipients with myeloid malignancies (49%), by Kröger et al³⁰ in both related and unrelated recipients (37%), by Wong et al³¹ in unrelated recipients (41%), by Bertz et al³² in both related and unrelated recipients (55.5%), and by Sayer et al³³ in related and unrelated recipients (42%).

Infections in the absence of GvHD caused an overall nonrelapse mortality rate of 2% for related recipients and 11% for unrelated recipients, respectively. Pneumonias were the most frequent infections. These findings call for better infection prevention and control, in particular, in elderly individuals. We recently compared morbidity and nonrelapse mortalities after related or unrelated HCT following ablative or reduced conditioning HCT^29,34 and found both to be significantly increased among ablative recipients. Sierra et al³⁵ have described nonrelapse mortality of 43%, mostly within the first 100 days after conventional unrelated HCT in patients with a median age of 30 years (range, 1 to 55 years). Robin et al³⁶ reported a nonrelapse mortality of 22% in myeloablative related recipients with AML in CR, who had a median age of 27 years (range, 2 to 53 years). Among patients with AML in CR1 with a median age of 34 years (range, 20 to 57 years) undergoing non-T cell-depleted, HLA-matched HCT following Cy/TBI or Bu/Cy conditioning, nonrelapse mortalities were 23% to 25% at 1 year.³⁷ Wong et al³¹ described a 1 year nonrelapse mortality of 55% in patients with a median age of 60 years (range, 55 to 69 years) given reduced conditioning. A retrospective multicenter study published by Kröger et al³⁰ reported 45% nonrelapse mortality after unrelated HCT, following reduced conditioning. Sayer et al³³ described 33% nonrelapse mortality in patients with AML in CR or PR compared with 66% among patients with advanced disease.

From the data obtained in this analysis we conclude that HCT from related and unrelated donors after low-dose TBI is a promising and safe treatment for elderly patients and medically infirm younger patients with AML not eligible for conventional HCT.

	Appendix: Participating Centers

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Patients underwent transplantation at the Fred Hutchinson Cancer Research Center (Seattle, WA), University of Washington, Medical Center (Seattle, WA), Seattle Children's Regional Medical Center (Seattle, WA), Seattle Veterans Affairs Research Service Medical Center (Seattle, WA), Stanford University (Palo Alto, CA), University of Colorado (Denver, CO), University of Utah (Salt Lake City, UT), Baylor University (Dallas, TX), Oregon Health & Science University (Portland, OR), University of Arizona (Tucson, AR), University of Leipzig (Germany), University of Vienna (Austria), Hopital Henri Mondor, (Creteil, France), Hotel Dieu, (Paris, France), University of Torino, (Torino, Italy), and Kantonspital Basel (Switzerland).

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix: Participating Centers Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Dietger Niederwieser, Brenda M. Sandmaier, Michael B. Maris, Judith A. Shizuru, Hildegard Greinix, Catherine Cordonnier, Alois Gratwohl, Thoralf Lange, Haifa Al-Ali, David Maloney, Peter McSweeney, Ed Agura, Richard T Maziarz, Finn Petersen, Rainer Storb Financial support: Bernard Rio Administrative support: Dietger Niederwieser, Barry Storer, Benedetto Bruno Provision of study materials or patients: Dietger Niederwieser, Brenda M. Sandmaier, Michael B. Maris, Judith A. Shizuru, Catherine Cordonnier, Richard T. Maziarz, Finn Petersen, Rainer Storb Collection and assembly of data: Ute Hegenbart, Dietger Niederwieser, Alois Gratwohl, Haifa Al-Ali, Ed Agura, Benedetto Bruno, Finn Petersen, Rainer Storb Data analysis and interpretation: Dietger Niederwieser, Brenda M. Sandmaier, Michael B. Maris, Thoralf Lange, Haifa Al-Ali, Barry Storer, Thomas Chauncey, Ed Agura Manuscript writing: Ute Hegenbart, Dietger Niederwieser, Judith A. Shizuru, Hildegard Greinix, Catherine Cordonnier, Bernard Rio, Thoralf Lange, Haifa Al-Ali, Peter McSweeney, Richard T. Maziarz, Rainer Storb Final approval of manuscript: Ute Hegenbart, Dietger Niederwieser, Brenda M. Sandmaier, Michael B. Maris, Judith A. Shizuru, Hildegard Greinix, Catherine Cordonnier, Bernard Rio, Alois Gratwohl, Thoralf Lange, Haifa Al-Ali, Barry Storer, David Maloney, Peter McSweeney, Thomas Chauncey, Ed Agura, Richard T. Maziarz, Finn Petersen, Rainer Storb, Benedetto Bruno

 

	ACKNOWLEDGMENTS

 
We thank Monica Stuart, Wolfram Pönisch, Leante Grommisch, Effie Petersdorf, and Elliot Epner, as well as Heather Hildebrandt, Debbie Bassuk, Steve Minor, Mary Hinds, John Sedgwick, Helen Crawford, and Bonnie Larson for their invaluable help in making the study possible.

	NOTES

 
Supported by grants CA 18029, CA 15704, CA 78902, and HL 36444 from the National Institutes of Health, Bethesda, MD and by the EU grant European Leukemia Net and the Swiss National Research Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix: Participating Centers Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted July 3, 2005; accepted October 28, 2005.

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