Originally published as JCO Early Release 10.1200/JCO.2006.07.0953 on January 16 2007

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Partially Matched, Nonmyeloablative Allogeneic Transplantation: Clinical Outcomes and Immune Reconstitution

David A. Rizzieri, Liang Piu Koh, Gwynn D. Long, Cristina Gasparetto, Keith M. Sullivan, Mitchell Horwitz, John Chute, Clayton Smith, Jerald Z. Gong, Anand Lagoo, Donna Niedzwiecki, Jeannette M. Dowell, Barbara Waters-Pick, CongXiao Liu, Dawn Marshall, James J. Vredenburgh, Jon Gockerman, Carlos Decastro, Joseph Moore, Nelson J. Chao

From the Department of Medicine, Division of Cellular Therapy; Department of Biostatistics; Department of Pathology, Division of Hematopathology; and Department of Medicine, Division of Oncology, Duke University Medical Center, Durham, NC; and the Department of Medicine, Division of Stem Cell Transplantation, Vancouver University, Vancouver, British Columbia, Canada

Address reprint requests to David A. Rizzieri, MD, Box 3961, Duke University Medical Center, Durham, NC 27710; e-mail: rizzi003{at}mc.duke.edu

	ABSTRACT

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PURPOSE: Allogeneic transplantation is typically limited to younger patients having a matched donor. To allow a donor to be found for nearly all patients, we have used a nonmyeloablative conditioning regimen in conjunction with stem cells from a related donor with one fully mismatched HLA haplotype.

PATIENTS AND METHODS: Fludarabine, cyclophosphamide, and alemtuzumab were used as the preparatory regimen. Additional graft-versus-host disease (GVHD) prophylaxis included mycophenolate with or without cyclosporine. Patients with persistence of disease had a donor lymphocyte boost planned. Toxicities, engraftment, response, survival, and immune recovery are reported.

RESULTS: Forty-nine patients with hematologic malignancies or marrow failure and no other available donors were enrolled. Ninety-four percent of patients had successful engraftment, and 8% had secondary graft failure. The treatment-related mortality rate was 10.2%, and 8% of patients had severe GVHD. Encouraging evidence of quantitative lymphocyte recovery through expansion of transplanted T cells was noted by 3 to 6 months. Seventy-five percent of patients attained a complete remission, and 1-year survival rate was 31% (95% CI, 18% to 44%). A standard-risk group of 19 patients with aplasia or in remission at transplantation demonstrated a 63% 1-year survival rate (95% CI, 38% to 80%) and 2.9-year median overall survival time (95% CI, 6.2 to 48 months).

CONCLUSION: Nonmyeloablative therapy using haploidentical family member donors is feasible because the main obstacles of GVHD and graft rejection are manageable, allowing readily available stem-cell donors to be found for nearly all patients. Further qualitative and quantitative improvement in immune recovery is needed to address the high rate of relapse and risk of severe infections.

	INTRODUCTION

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Allogeneic stem-cell transplantation (SCT) has traditionally been limited to younger, healthier patients with a matched donor.^1-4 We and others have successfully used a nonmyeloablative regimen combined with alemtuzumab for T-cell depletion of the host and donor to allow reliable engraftment and decreased graft-versus-host disease (GVHD) in those with a matched sibling or matched unrelated donor.^5-11 Using stem cells from haploidentical family members would further extend this form of SCT by providing a readily available source of hematopoietic stem cells for most patients. Prior work using ablative therapy with haploidentical or mismatched cord blood donors has been successful, but this method carries the risk of severe treatment-related morbidity and mortality, limiting its use.^12-15 Although past reports combining T-cell depletion and haploidentical donor cells with nonmyeloablative therapies have been discouraging,^16-18 this article extends the prior work and reports the largest series assessing outcomes and immune reconstitution in successful nonmyeloablative, haploidentical transplantation. This approach significantly expands the pool of patients who may benefit from SCT and provides a framework for successful allogeneic therapy using haploidentical family members.

	PATIENTS AND METHODS

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Patient and Donor Selection
Patients with relapsed or refractory hematologic malignancies or advanced myeloproliferative disorders were eligible. Patients did not have a matched related or unrelated donor readily available and were not considered candidates for ablative allogeneic therapy as a result of having other comorbidities, known recent Aspergillus infection, advanced age, or prior high-dose therapy. Patients also did not have a single cord blood unit of sufficient HLA match and cell number to allow transplantation. Pulmonary function testing with a single-breath diffusing capacity of 40% predicted, cardiac ejection fraction of 40%, negative HIV test, and performance status of 2 were also required. The protocol was approved by the Duke University Medical Center institutional review board, and all patients and donors provided informed consent.

Preparative Regimen
Donors received filgrastim 8 µg/kg twice daily beginning 5 days before pheresis and continuing until apheresis was completed. The preparative regimen, based on adjusted ideal body weight, included alemtuzumab 20 mg/d in 250 mL of dextrose 5% in normal saline infused over 3 hours on days –4 to 0; fludarabine 30 mg/m² per day infused over 30 minutes on days –5 to –2; cyclophosphamide 500 mg/m² per day infused over 1 hour on days –5 to –2; and filgrastim 5 µg/kg (rounded to nearest vial) administered on day +1 until absolute neutrophil count was more than 1 x 10⁹/L for 2 days. All 49 patients received mycophenolate 1 g orally twice daily for 45 days. Early results were encouraging, but to further increase GVHD prophylaxis, the final 25 enrolled patients also received cyclosporine with dose adjusted to a plasma level of 200 ng/mL for the first 60 days. Donor lymphocyte infusions (DLI) were planned for all patients who had persistence of disease after transplantation if they did not have severe GVHD.

All purging was accomplished in vivo after stem infusion into the patient; however, in vitro estimates of the degree of T-cell purging were performed in 33 patients. A 5-mL aliquot of patient serum and pheresed donor cells were mixed to a cell suspension containing 25% serum volume and incubated for 30 minutes at 37°C with 2 µg of alemtuzumab followed by a flow analysis for viability of the cellular suspension using the 7-aminoactinomycin-D (7AAD) method.^19,20

Statistical Methods
The primary objective of this study was to evaluate feasibility in terms of mortality, occurrence of acute GVHD, grade 3 or 4 toxicity, and engraftment. Mortality from any cause except progression within the first 100 days was assessed for treatment-related mortality (TRM). For evaluation of acute GVHD, the occurrence of acute GVHD could be estimated to within +0.132 with 95% confidence. Toxicities were formally graded twice weekly using the National Cancer Institute Common Toxicity Criteria (version 3.0).²¹ The regimen would be considered tolerable if the upper bound of the one-sided 95% confidence limit for the proportion of patients experiencing unacceptable grade 3 or 4 toxicity was 0.54. Early engraftment was evaluated when the absolute neutrophil count was more than 500/µL, platelets were more than 20,000/µL, and hemoglobin level was greater than 8 g/dL. Short tandem repeat analysis revealing at least 2.5% donor cells was required to consider allogeneic engraftment having occurred, as reported in our prior publication.¹⁵ The null hypothesis that the rate of failure to engraft was 30% (null hypothesis: P .30) was compared against the alternative hypothesis that this rate was 50% (alternative hypothesis: P .50). The power to detect the alternative hypothesis under this design was 0.79, and the significance level was approximately 0.05. Testing for engraftment and correlative studies was typically performed at early recovery (around 2 weeks) and at 1.5, 3, 6, and 12 months after transplantation.

After meeting initial feasibility milestones, additional accrual was completed to provide further information for the secondary end points of survival and immune recovery. Response was assessed using standardized criteria.^22,23 Overall survival was assessed from the first day of transplantation to September 6, 2006, and recurrence-free survival was measured in all patients who attained a complete response from the first day of transplantation until progression or death.

Immune Recovery Assays
All lymphocyte subset analyses were performed using three- and four-color flow cytometry analysis from peripheral blood. Immunoscope assays (CDR3 spectra typing) were performed as previously described with oligonucleotide primers specific for each of 23 Vß gene segments and the Cß1 segment. The number of peaks was counted within each Vß family, and the total fluorescence intensity under each peak was calculated across each Vß family.²⁴ Evaluation for the development of newly educated T cells was performed using single-joint T-cell receptor excision circle (TREC) assays from samples of peripheral-blood mononuclear cells according to a method previously described with a limit of detection of more than 100 sjTRECs/µg DNA.^25,26

	RESULTS

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Forty-nine patients were treated; the median age was 48 years, and seven patients were older than 60 years. In general, the patients were a heavily pretreated group, with a median of three prior regimens, and only two patients had no prior cytotoxic therapy; 12 patients had prior high-dose therapy requiring autologous hematopoietic support. Sixty-one percent of patients had refractory disease at study entry, whereas only 14% were in first remission or previously untreated (Tables 1 and 2). The median duration of follow-up of surviving patients was 40 months (range, 4 to 48 months).

Recovery and Engraftment
Myeloid recovery occurred within 2 weeks, and the absolute neutrophil count was less than 0.5 x 10⁶/L for a median of 8 days (range, 0 to 30 days). The median number of days of platelet counts less than 20 x 10⁹/L was 3 days (range, 0 to 21 days), and 18 patients never had a platelet count below this threshold. Short tandem repeat analysis revealed that donor cells accounted for 87% of the hematopoietic activity by the first 6 weeks after infusion (Table 2). Interestingly, as examined by CD3 separation, there was similar engraftment kinetics in both the myeloid and lymphoid compartments (data not shown). Three patients (6%) experienced primary graft failure. Both of the previously untreated patients experienced engraftment. Four patients (8%) experienced secondary graft failure.

Toxicities
Considering the primarily older, more infirmed population targeted in this feasibility trial, the therapy was generally well tolerated in the outpatient setting, with transient grade 2 to 3 nausea/vomiting or diarrhea in 14 patients, worsening cardiac function in four patients, transient renal insufficiency of grade 2 to 3 in six patients, and dialysis requirement in one patient. TRM was low, with five deaths (10.2%) not related to progressive disease (four from infections and one from neurotoxicity) in the first 100 days (Fig 1A). Twenty-five percent of patients experienced a severe infection, whereas 86% experienced reactivated cytomegalovirus, although monitoring allowed for early institution of therapy, limiting cytomegalovirus disease to seven patients (14%; Table 3). Mild GVHD of the skin was common and controlled with a short course of corticosteroids. Overall, 16% of patients experienced grade 2 to 4 GVHD, whereas only 8% had severe grade 3 to 4 acute GVHD (Table 4 and Fig 1A). Seven patients (14%) experienced chronic GVHD or failure to thrive. There was no difference in these rates between patients who did and did not have cyclosporine added or between the 14 patients who had a DLI and patients who did not have a DLI; therefore, all 49 patients are presented as one group.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Cumulative incidence graphs using Kaplan-Meier estimates. (A) Overall graft-versus-host disease (GVHD; grade 3 or 4) and treatment-related mortality (TRM) for all 49 patients (crude rates of severe GVHD and TRM were 8% and 10.4%, respectively). (B) Nonrelapse mortality for all patients (crude rate = 15 of 49 patients, 31%). (C) Recurrence-free survival (RFS) and overall survival (OS) for all patients. (D) RFS and OS for the 19 standard-risk patients.

Retrospectively, we found that 19 of 49 patients were standard-risk patients in first or second partial remission or complete remission for myelodysplasia, high-risk leukemia, or severe aplastic anemia. This subgroup could not undergo ablation as a result of not having a matched donor (related or unrelated), was older than 60 years, had known fungal infection at study entry, or had poor lung or cardiac function. Despite these limitations, they had a 1-year recurrence-free survival rate of 59% (95% CI, 32% to 78%) and a 1-year overall survival rate of 63% (95% CI, 38% to 80%; Fig 1D). The median recurrence-free and overall survival time was 2.9 years (95% CI, 6.2 to 48 months). Larger studies with more standard-risk patients are needed to confirm these encouraging results.

Immune Reconstitution
Figure 2 represents the immune recovery data from all treated patients. Phenotypic recovery is represented in Figure 2 comparing the recovery of CD4⁺, CD8⁺, CD56⁺, CD45RO⁺, and CD45RA⁺ cells between patients with and without acute GVHD on immunosuppressive therapy. Patients without GVHD were noted to have cellular recovery within 3 to 6 months and consistently had improved recovery compared with patients with GVHD, although the overall lymphocyte numbers were still low. Similarly, immunoscope analysis of the Vß family of T cells revealed a consistent pattern favoring patients without GVHD. Figure 3 is a summary of each Vß family among all patients. Appendix Figure A1 (online only) is a representative analysis from one patient without GVHD and one patient with GVHD to convey not only the difference in peaks per family as noted in Figure 3, but also the area under the curve of each individual family. Appendix Figure A1 depicts superior numbers of T cells and a more Gaussian-like distribution for each individual Vß family in patients without GVHD. Our engraftment studies indicate that nearly all of the lymphocytes were of donor origin, even early in this recovery period (Table 2). Only one of 11 patients had measurable TRECs at 6 months, and two of five patients had measurable TRECs at 1 year.

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Phenotypic median lymphocyte count recovery (with SE bars) from all patients enrolled onto the study. This figure compares the recovery of (A) CD4+, (B) CD8+, (C) CD45RO+ and CD45RA+, and (D) CD56+ cells between patients with and without acute graft-versus-host disease (GVHD) on immunosuppressive therapy. Note the consistent improvement in recovery of lymphocyte subsets in patients without GVHD.

View larger version (38K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Spectratyping results noting the variety and numbers of T cells in the Vß family at (A) pre-transplant baseline, (B) graft-versus-host disease (GVHD) 6 weeks, (C) GVHD 3 months, (D) GVHD 6 months, and (E) GVHD 12 months. Blue bars (with SE lines) represent the median peaks/family in patients without GVHD, whereas the gold bars represent results in patients with GVHD and on immune suppressive therapy. Note the improved recovery of the patients without GVHD.

	DISCUSSION

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Recent studies using matched unrelated donors note similar engraftment rates compared with the rate of 94% in this report.^28-30 However, nonmyeloablative therapy using matched unrelated donors typically results in grade 2 to 4 GVHD rates of 40% to 65%, grade 3 to 4 GVHD of at least 25%, and chronic GVHD rates of 40% to 70%^18,27,28,30; our rates were 16%, 8%, and 14%, respectively. Important advances in working with haploidentical donors with a reduced-intensity regimen have been recently reported by Aversa et al.³¹ Their regimen used 8 Gy of total-body radiation with thiotepa (5 mg/kg/d for 2 days), fludarabine (40 mg/m²/d for 5 days), and antithymocyte globulin. Donor cells were T depleted using a CD34⁺ selection device, and no post-transplantation immune suppression was administered. This group showed successful engraftment and low rates of TRM and GVHD in the same range as in the current study. Relapse remained a problem, with patients undergoing transplantation with active disease rarely maintaining a long disease-free state and patients undergoing transplantation in remission having approximately a 50% 2-year event-free survival rate. Our trial uses a truly nonmyeloablative approach in patients who were, on average, older than the patients in the study by Aversa et al³¹ (median age, 48 years in the current study v 33 years), and the majority of our patients had active disease at study entry. Despite this, our 1-year overall survival rate of 31% for all patients and 1-year survival rate of 63% and median survival time of 2.9 years in the subgroup of standard-risk patients are encouraging. Developing a regimen that allows older, more infirm patients to benefit from haploidentical allogeneic therapy while maintaining an often fragile state of health provides a foundation for future betterment.

The use of T-cell depletion raises the concern of poor response rates and increased relapse rates. However, not all T-cell–depleting methods are necessarily equal in this regard. Although past reports citing nonmatched, uncontrolled data suggest that alemtuzumab may be associated with increased relapse rates,^32,33 a matched historically controlled comparative study has been published noting that the relapse rate using alemtuzumab in ablative therapy is no different than non–T-cell–depleted regimens.⁷ This encouraging result may, in part, be derived from the known benefits of alemtuzumab sparing CD56⁺ natural killer and cytotoxic T cells, while depleting CD8⁺ and CD4⁺ cells.^34,35 Natural killer cells are purported to play a major role in antitumor effects after transplantation.^36-38 Furthermore, using this regimen with haploidentical donors will allow future studies to evaluate the role of killer inhibitory receptors in antitumor effects as well as noninherited maternal antigens, both of which have been recently implicated in improved outcomes.^39,40

Improving long-term outcomes with nonmyeloablative therapies depends, in part, on developing methods after transplantation to more effectively eradicate minimal residual disease. Understanding immune reconstitution is critical in making these advances, and little detailed information is available after nonmyeloablative allogeneic therapy, particularly after a T-cell–depleted process. We have shown that lymphocyte recovery is similar to past reports^41,42 and occurs 3 to 6 months after therapy with an early recovery of CD56⁺ cells (natural killer cells), a point at which our preliminary data suggest newly educated T cells are not evident. A valid functional analysis of immune recovery remains problematic because in vitro correlations to clinical results are lacking for available tests such as tetanus toxoid responses, fast immune assays, or enzyme-linked immunosorbent spot assays. Ultimately, clinical outcomes are the key to success, with the toxicity analysis suggesting a reasonably well-tolerated procedure and an encouraging long-term disease-free and overall survival noted in the standard-risk patients enrolled onto this feasibility study. Importantly, we have shown the expected negative effects on immune recovery (in terms of rate of lymphocyte recovery) that GVHD and immunosuppressive agents have in the nonmyeloablative setting, as has already been shown in non–T-cell–depleted studies and in the ablative setting. Our results indicate that, despite T-cell depletion, few patients experience severe GVHD and prolonged use of immunosuppressive agents, and lymphocyte recovery is notable even within a few months of recovery. The inclusion of planned DLIs for patients with persistent disease may also have played a role because DLI has been shown to hasten immune recovery,⁴³ an aspect that is difficult or impossible to add in the matched unrelated donor or cord blood setting. Because this regimen results in minimal rates of severe GVHD compared with other reports, it provides a foundation for comparison with alternative approaches promoting post-transplantation immune recovery.

The high engraftment rate (94%) and complete response rate (75%) and the low severe acute GVHD rate (8%) are encouraging. With 4.25 years of median follow-up time for surviving patients, the 31% 1-year overall survival rate compares favorably with other feasibility studies of ablative haploidentical (28% survival rate with median follow-up of 18 months)¹² or cord blood transplantation (28% survival rate with median follow-up of 22 months).¹⁵ Furthermore, in the subgroup of standard-risk patients, the 63% 1-year median survival rate and 2.9-year median survival time are very encouraging and compare quite favorably with reports using alternative matched unrelated donors or cord blood.^28,30,44 This report demonstrates the feasibility of using haploidentical family member donors for nonmyeloablative allogeneic transplantation in older, more infirm patients, providing a readily available donor for nearly all patients who are considering allogeneic therapy.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: David A. Rizzieri, Speaker's Bureau for Berlex Oncology Research Funds: David A. Rizzieri, Amgen, Berlex; Cristina Gasparetto, Research support from Berlex Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: David A. Rizzieri

Financial support: David A. Rizzieri, Nelson J. Chao

Provision of study materials or patients: David A. Rizzieri, Gwynn D. Long, Cristina Gasparetto, Keith M. Sullivan, Mitchell Horwitz, Jerald Z. Gong, Anand Lagoo, James J. Vredenburgh, Jon Gockerman, Carlos Decastro, Joseph Moore

Collection and assembly of data: David A. Rizzieri, Liang Piu Koh, Keith M. Sullivan, John Chute, Clayton Smith, Anand Lagoo, Barbara Waters-Pick, Cong Xiao Liu, Dawn Marshall, Nelson J. Chao

Data analysis and interpretation: David A. Rizzieri, Liang Piu Koh, Keith M. Sullivan, Donna Niedzwiecki, Jeannette M. Dowell, CongXiao Liu, Dawn Marshall, Nelson J. Chao

Manuscript writing: David A. Rizzieri, Liang Piu Koh, Gwynn D. Long, Cristina Gasparetto, Keith M. Sullivan, Mitchell Horwitz, John Chute, Clayton Smith, Jerald Z. Gong, Anand Lagoo, Donna Niedzwiecki, Jeannette M. Dowell, Dawn Marshall, James J. Vredenburgh, Jon Gockerman, Carlos Decastro, Joseph Moore, Nelson J. Chao

Final approval of manuscript: David A. Rizzieri

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Spectratyping results from two patients 6 months after transplantation. A normal sample from a healthy patient would show a Gaussian distribution for each family. (A) This patient did not have graft-versus-host disease (GVHD). (B) This patient had GVHD and, therefore, was also on immune suppression therapy.

	ACKNOWLEDGMENTS

 
We thank the residents, fellows, and nurses in the Bone Marrow Transplant Unit for the fine care of our patients; the referring physicians for their cooperation and support; and Rhonda Garrett for her significant support in data management.

	NOTES

 
published online ahead of print at www.jco.org on January 16, 2007.

Supported in part by National Institutes of Health Grants No. 5K23RR16063-01 (D.A.R.), 2PO-1CA47741 (N.J.C.), and M01-RR30 (National Center for Research Resources, Clinical Research), the Lisa Stafford Memorial Young Investigator Award (D.A.R.), Amgen Inc, and Berlex Laboratories Inc.

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

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Submitted April 25, 2006; accepted November 29, 2006.

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