Reduced-Intensity Conditioning followed by Peripheral Blood Stem Cell Transplantation for Adult Patients with High-Risk Acute Lymphoblastic Leukemia

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Inclusion Criteria
  • Patients
  • Treatment Regimen
  • Statistics
• Results
  • Engraftment
  • GVHD
  • Outcomes
• Discussion
• Acknowledgments
• Authorship
• References
• Copyright

Acute lymphoblastic leukemia (ALL) with high-risk features has a poor prognosis in adults despite aggressive chemotherapy. Reduced-intensity conditioning (RIC) is a lower toxicity alternative for high-risk patients requiring hematopoietic cell transplantation (HCT); however, it has not been widely used for ALL. We conducted a retrospective study of 24 high-risk adult ALL patients who received an RIC regimen of fludarabine (Flu)/melphalan (Mel) prior to allogeneic peripheral blood stem cell transplantation (PBSCT) between 6/14/02 and 6/15/07 at the City of Hope. Indications for the RIC regimen were: (1) aged 50 years or older (42%), (2) compromised organ function (54%), or (3) recipient of a previous HCT (37.5%). Patients had a median age of 47.5 years and the median follow-up was 28.5 months for living patients. Both overall survival (OS) and disease-free survival (DFS) at 2 years was 61.5%. Relapse incidence was 21.1% and nonrelapse mortality (NRM) was 21.5% at 2 years. Chronic graft-versus-host (cGVHD) developed in 86% of evaluable patients. In this series, no significant correlations were made between outcomes and patient age, presence of Philadelphia chromosome, relatedness of donor source, or prior HCT. These high survival rates for high-risk ALL patients following RIC HCT may offer a promising option for patients not eligible for a standard myeloablative transplant.

Key Words: Reduced-intensity, Transplant, ALL, Acute lymphoblastic leukemia

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Introduction 

Acute lymphoblastic leukemia (ALL) has a poor prognosis in adult patients, with a 5-year overall survival (OS) rate of 39% to 50% despite aggressive chemotherapy 1, 2, 3, and only 15% for patients over 50 years of age [3]. In patients with high-risk disease, as determined by age, cytogenetics, remission status, and/or response to induction therapy, survival outcomes are even worse 1, 2, 3. According to the MRC/ECOG ALL Trial of chemotherapy versus autologous and allogeneic transplant, allogeneic hematopoietic cell transplantation (HCT) confers the greatest durable benefit for standard-risk adult patients and is more effective than either chemotherapy or autologous transplant [4]. Goldstone et al. [4] also show, however, that for patients over 45 years and others with high-risk ALL, a high nonrelapse mortality (NRM) of 36% offsets any potential survival advantage of the reduced relapse rate conferred by myeloablative (MA) transplant. Patients requiring transplants who are over the age of 50 years, have impaired organ function, or have had previous ablative therapy are unable to withstand the toxicity of the MA protocols that are standard of care.

In the last 10 years, the goal of reducing treatment-related mortality (TRM) has led to the investigation of a variety of reduced-intensity, nonmyeloablative conditioning (RIC, NMA) protocols for allogeneic HCT in patients with multiple hematologic malignancies 5, 6, 7, 8. In a study comparing RIC to standard HCT, NRM (22% versus 30%) and OS (59% versus 52%) were comparable [8]. Similar to observations in the MA transplant setting, Mohty et al. [7] describe a strong association of chronic graft-versus-host disease (cGVHD) with a reduction in relapse incidence from 55% to 30%, suggesting a primary role for graft-versus-leukemia (GVL) in the achievement of remission via RIC HCT.

Four small (22-33 patients) prospective studies 9, 10, 11, 12 and a larger (97 patients) retrospective study [13] have attempted to assess the feasibility and effectiveness of RIC specifically for treatment of ALL in high-risk populations. The 2-year OS rates for these studies average 32% (median: 31%, range: 18%-50%), with variable, but high, relapse rates and TRM, depending upon remission status. Consensus conclusions from these studies appear to be that improved survival is associated with RIC transplant during first complete remission (CR1) and that relapse incidence (RI) is lower for patients exhibiting GVHD.

In most published studies of RIC in ALL 9, 10, 11, 13, multiple sources of hematopoietic stem cells (HSCs) and pretransplant conditioning regimens were included in the same data set, making it difficult to obtain the best and most consistent results. In this study, we have removed the issue of transplantation regimen variation; all patients were treated at the City of Hope with peripheral blood stem cell transplantation (PBSCT) following the same RIC regimen. Based on this more homogeneous treatment and stem cell source, we report a high survival rate among high-risk ALL patients receiving RIC.

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Patients and Methods 

Inclusion Criteria 

A retrospective analysis was conducted on 24 high-risk ALL patients treated between 6/14/02 and 6/15/07 with a uniform RIC SCT protocol at the City of Hope. The indications for the RIC regimen were 1 or more of the following: (1) patient aged 50 years or older (42%), (2) compromised organ function (54%), or (3) recipient of a previous HCT (37.5%). Indications for HCT during CR1 included age over 35, high white blood cell (WBC) count (>50,000) at diagnosis, multiple rounds of induction chemotherapy required to achieve remission, and/or poor prognosis cytogenetics (e.g., Philadelphia chromosome or t[4;11][q21;q23]). Cytogenetic risk level, based on Pullarkat et al. [14], is indicated in Table 1 as Level 2, 3, 4 or Philadelphia chromosome positive (Ph⁺) (in increasing order of severity). The City of Hope institutional review board approved the retrospective study and analysis of this patient case series.

Table 1. RIC Patient Data

Pt No.	Sex	Age at RIC	Compromised Organ Systems	PriorHCT	Status at RIC	Donor Type	GVHD Prophylaxis	Cytogenetic Risk Level∗	aGVHD Grade	cGVHD Grade	Outcome dd=death on day rd=relapse on day	Survivor KPS (%)
1	F	45	none	Yes	CR1	MUD	TAC/SIR/MTX	Level 2	Grade III	Extensive	infection: dd 195	NA
2	F	62	none	No	CR1	MUD	CsA/MMF/MTX	Ph+	None	Extensive	alive in remission	90%
3	F	57	none	No	CR1	MUD	CsA/MMF/MTX	Ph+	Grade III	None	infection: dd 245	NA
4	F	57	none	No	CR1	SIB	CsA/MMF	Ph+	Grade II	Extensive	relapsed, rd 857alive after second RIC	90%
5	F	56	renal	No	CR1	SIB	TAC/SIR	Ph+	None	Limited	alive in remission	80%
6	M	61	cardiac	No	CR1	MUD	CsA/MMF/MTX	Ph+	Grade II	Limited	alive in remission	90%
7	F	62	cardiac, lung	No	CR1	SIB	TAC/SIR	Unknown	Grade II	Limited	alive in remission	80%
8	F	54	renal, cardiac	No	CR1	MUD	TAC/SIR/MTX	Level 3	Grade II	Limited	alive in remission	90%
9	F	46	renal, cardiac	No	CR1	MUD	TAC/SIR/MTX	Level 2	Grade II	NA	multiple organ failure: dd 34	NA
10	M	49	prior chemo/radiation	No	CR1	MUD	TAC/SIR	Level 3	Grade I	Limited	alive in remission	100%
11	M	38	none	Yes	CR1†	MUD	CsA/MMF/MTX	Ph+	Grade IV	NA	idiopathic interstitial pneumonitis: dd 29	NA
12	M	28	spine irradiation	No	CR2	MUD	CsA/MMF/MTX	Unknown	Grade I	Extensive	alive in remission	Unknown
13	F	68	none	Yes	CR2	MUD	ATG/CsA/MMF	Ph+	Grade II	None	disease progression: rd 532, dd 570	NA
14	F	31	none	Yes	CR2	SIB	TAC/SIR	Unknown	None	Extensive	disease progression: rd 96, dd 283	NA
15	F	41	lung	No	CR2	MUD	TAC/SIR/MTX	Level 2	Grade III	Extensive	disease progression: rd 207, dd 209	NA
16	F	50	none	Yes	CR2	MUD	CsA/MMF/MTX	Level 2	Grade II	Extensive	alive in remission	90%
17	F	54	pneumonia	No	Induction Failure	SIB	TAC/SIR	Ph+	Grade I	Extensive	alive in remission	80%
18	M	32	none	Yes	R1	MUD	CsA/MMF/MTX	Ph+	None	Extensive	alive in remission	90%
19	F	43	cirrhosis of liver	Yes	R1	SIB	CsA/MMF	Level 2	Grade II	Extensive	alive in remission	100%
20	F	48	none	Yes	R1	MUD	CsA/MMF/MTX	Ph+	Grade II	Extensive	disease progression: rd 156,dd 162	NA
21	M	42	none	Yes	R2	MUD	TAC/SIR/MTX	Level 2	None	None	alive in remission	90%
22	M	47	pneumonia, leukoencephalopathy	No	≥CR3	SIB	TAC/SIR	Level 2	Grade III	NA	leukoencephalopathy dd 53	NA
23	M	23	cardiac, leukoencephalopathy	No	≥CR3	SIB	TAC/SIR	Unknown	None	Extensive	alive in remission	90%
24	M	27	cardiac, lung	No	≥CR3	MUD	TAC/SIR/MTX	Level 2	Grade II	Extensive	alive in remission	90%

KPS indicates Karnofsky Performance Status score (defined in [18]); CR, complete remission; MUD, matched unrelated donor; TAC, tacrolimus; SIR, sirolimus; MTX, methotrexate; NA, not applicable; CsA, cyclosporine; MMF, mycophenylate mofetil; Ph+, Philadelphia chromosome positive; SIB, sibling donor; ATG, antithymocyte globulin; R, remission; RIC, reduced-intensity conditioning; aGVHD, acute graft-versus-host disease; cGVHD, chronic graft-versus-host disease.

Patients 

Salient patient characteristics for all 24 patients are displayed in Table 1. Fifteen women and 9 men were part of the study, with a median age of 47.5 years (range: 23-68 years). Seven patients (29%) had a previous allogeneic HCT and 2 (8%) had a previous autologous HCT. In addition to the high-risk factors for which they were included in this study, the patient population exhibited additional risk factors that could affect outcome: 67% of the PBSC donors were unrelated to the recipients, 54% of patients were beyond CR1 at the time of transplant, and 42% were Ph⁺. Three patients had ALL that was secondary to a prior malignancy: patient #1 had prior multiple myeloma (MM), #4 breast cancer, and #10 had both a history of chronic lymphocytic leukemia (CLL) and germ cell cancer. One patient, #9, also had a coexisting myelodysplastic syndrome (MDS) at the time of transplant.

Listed first in Table 1 are the 10 patients in CR1 (42%), followed by 1 CR1 patient (#11) who was not in molecular remission (4%), 4 patients in second complete remission (CR2, 17%), 1 induction failure (4%), 3 in first relapse (R1, 12%), 1 in second relapse (R2, 4%), and 4 in third CR or beyond (≥CR3, 17%). For patients in CR1, the median time between remission and transplant was 2.3 months (range: 0.5-5.7), 40% required 2 courses of chemotherapy to achieve remission and the median WBC at diagnosis was 21.5 (range: 0.6-70). Patients not in remission at the time of transplant had a median WBC prior to conditioning of 3.3 (range: 0.9-7.8), a median of 1% blasts in the bone marrow (BM) (range: 0-15), and a median of 0% blasts in the blood (range: 0-21).

Matched sibling donors were available for 8 of the 24 (33%) patients in the study. For the 16 patients lacking suitable related donors, HLA matched unrelated donors (MUDs) were successfully identified through the National Marrow Donor Program (NMDP). HLA typing was performed using polymerase chain reaction (PCR) sequence-specific primers (SSP) or PCR sequence-specific oligonucleotide probe (SSOP) techniques. Of the MUD transplants, mismatches were as follows: 10 patients were matched at 10 of 10 loci, 3 patients had 2 antigen mismatches, 1 patient was allele mismatched, and 1 patient had 2 allele mismatches and an antigen mismatch.

Treatment Regimen 

The RIC regimen for all patients consisted of i.v. Flu at 25mg/m² daily for 5 days followed by i.v. melphalan (Mel) at 140mg/m² for 1 day. Subsequently, patients received allogeneic PBSC mobilized with granulocyte colony stimulating factor (G-CSF). Eight of the 10 Ph⁺ patients were treated with thymidine kinase inhibitors (TKI) pre- and/or post-transplant. Table 2 shows details of treatment for Ph⁺ patients, including type and duration of TKI therapy.

Table 2. Ph⁺ Patient Data

TKI indicates thymidine kinase inhibitor; HCT, hematopoietic cell transplantation; CR, complete remission; mol+, molecular positive; Ind, induction; IP, interstitial pneumonitis; RIC, reduced-intensity conditioning.

The GVHD prophylactic treatment regimen and the maximal extent of acute (aGVHD) and cGVHD manifestations are listed in Table 1 for each patient. Prophylactic treatment of GVHD varied between patients depending on their HLA match and the available protocols at the time of transplant and included: cyclosporine (CsA) plus mycophenylate mofetil (MMF) in 2 patients, CsA/MMF plus methotrexate (MTX) in 8 patients, CsA/MMF plus antithymocyte globulin (ATG) in 1 patient, tacrolimus plus sirolimus in 7 patients, and tacrolimus/sirolimus plus MTX in 6 patients. No patient in this study group was treated using donor leukocyte infusion (DLI).

Statistics 

Survival estimates were calculated based on the product-limit method, and 95% confidence intervals were calculated using the logit transformation and the Greenwood variance estimate [15]. Differences between survival curves were assessed by the log rank test. The significance of demographic/treatment features collected from HCT recipients was assessed using survival analysis and univariate Cox regression analysis [16]. The list of features included was determined from a literature review that identified factors found to be associated with survival and disease relapse in patients treated with allogeneic RIC HCT. Statistical significance was defined at the value of P ≤.05.

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Results 

Engraftment 

All 24 patients engrafted successfully. The median time, postengraftment, to reach an absolute neutrophil count (ANC) of ≥500, was 15 days (range: 10-26 days), and a platelet count ≥20,000 was 16.5 days (range: 8-24 days). At day 30 postengraftment, short tandem repeat (STR) analysis of BM showed a median of 100% donor cells (range: 90%-100%).

GVHD 

Eighteen patients (75%) developed aGVHD, which was graded according to consensus criteria [17]. Three patients displayed grade I aGVHD, 15 had grade II-IV, with 5 of those suffering grade III or IV. Of the 21 patients evaluable 100 days postengraftment, 18 developed cGVHD (86%); 13 were classified with extensive disease, and 5 with limited cGVHD. Three patients did not develop any symptoms of cGVHD. The 3 patients not evaluable for cGVHD died prior to 100 days postengraftment. We also noted that 9 of the patients had cGVHD with acute features: 4 cases developed progressively from aGVHD, 3 were acute/chronic overlap syndromes, and 2 cases were delayed acute onset (after day100). Only 1 patient exhibited neither aGVHD (grade II or above) nor cGVHD (4%).

Outcomes 

Relapse and death events are reported as days post-HCT and cause of death is listed in Table 1 in the outcome column. Fifteen of the 24 patients were living and disease-free at analysis date, 1 of whom had relapsed (patient #4), but was disease-free 1 year after a second RIC transplant. Karnofsky Performance Status (KPS) scores [18] for survivors are listed in the last column, with all patients at 80% or above and able to carry on relatively normal activity. The KPS score for 1 surviving patient was unobtainable. Of the 13 surviving patients with cGVHD, at the date of analysis, 6 patients had active disease and remained on immunosuppressive therapy, 5 patients had inactive disease and were tapering medications (3 tacrolimus only), and 3 patients were completely off cGVHD medications. Duration of TKI therapy for Ph⁺ patients is shown in Table 2. TKI therapy was discontinued because of side effects, relapse, or with cessation of immunosuppressive therapy.

Median follow-up for living patients was 28.5 months (range: 12.8-72.5 months). OS and disease-free survival (DFS) at 2 years were both 61.5%, with a confidence interval (CI) of 48.1% to 72.5%. Survival curves for OS and DFS are displayed in Figure 1A and B, respectively. Figure 1B also shows the RI curve, with RI at 14.6% (CI of 5.8%-33.9%) at 1 year and 21.1% (CI of 10.2%-40.7%) at 2 years. NRM was 12.5% (CI of 4.8%-30.2%) at day 100, 21.5% (CI of 11.4%-38.3%) at 1 year and at 2 years, and is charted in Figure 1A. For NRM causes of death in individual patients, see Table 1.

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• Figure 1 

  RIC outcomes. Median follow-up was 28.5 months (A) OS and NRM, (B) DFS and RI.

The log rank test was applied to these data to determine whether there were any significant correlations between OS, DFS, RI, or NRM and known variables in the patient population. In contrast to other studies in the literature, at the date of analysis there were no significant relationships found. In particular, presence of Ph⁺ did not affect outcome (60% alive at time of analysis, see Table 2), nor did patient age ≥47 (75% living). Use of an unrelated donor and prior HCT also were not significant factors for outcome with 56% of MUD recipients and 44% of prior HCT recipients alive at the time of analysis. Comparison of patients in CR1 versus those beyond CR1 also yielded no significant differences with respect to outcome and the OS and RI curves are shown in Figure 2. Although some studies have shown a correlation between outcome and the occurrence of cGVHD, no meaningful tests could be performed comparing groups with and without symptoms of cGVHD, as the overwhelming majority of patients exhibited some level of GVHD. Of the 18 patients with cGVHD, 9 had some acute features, either progressive development, overlap syndrome, or delayed acute onset. There was no significant difference in outcomes for the 9 patients with acute features compared to the rest of the population.

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• Figure 2 

  CR1 versus >CR1 outcomes. Median follow-up for the 10 CR1 patients was 22.7 months and for the 14 patients at >CR1 was 16.4 months (A) OS and (B) RI.

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Discussion 

ALL is relatively rare in adults and its incidence increases dramatically with age. The cumulative incidence of ALL cases (per 100,000 of age-matched population) triples in the >50 age group compared to the 25-49 age group [19]. Additionally, the older patient population has a higher incidence of Ph⁺, exemplified by the Southwest Oncology Group (SWOG) study in which the median age is 32 years for the total study group and 47 years for Ph⁺ patients [14]. Older patients have a very poor prognosis without HCT, but are generally ineligible for MA transplants because of high NRM, as demonstrated in the MRC/ECOG ALL Trial [4]. Goldstone et al. [4] conclude, based on their results in older patients, that research on RIC transplant regimens in ALL is imperative to reduce morbidity and offer a viable alternative to high-risk patients. RIC has the potential to extend the benefit of transplant to those older patients for whom standard chemotherapy is not effective long term.

Based on the limited ability of DLI to produce a CR in relapsed ALL (only 18% as opposed to 60% for chronic myelogenous leukemia [CML]) [20], some believe that a GVL effect is not clinically important in ALL. Rowe and Goldstone [21] have suggested that the lack of response to DLI may be related to the fact that the DLI study involved patients in active relapse, whereas transplant patients are generally in remission, allowing for a more effective allogeneic response to tumor cells. Several transplant studies do, in fact, suggest that there is a therapeutic GVL effect in ALL, based on a correlation between GVHD and a decrease in relapse incidence among ALL patients, following both MA 22, 23 and RIC 7, 11 allogeneic HCT. The disparity between DLI-associated and transplant-associated GVL effects may also be because of differences in the ability of ALL blasts to present target antigens, the frequency of minor-antigen reactive T cell precursors, cell cycle kinetics, or susceptibility to lysis [24].

The development of RIC for ALL would give high-risk patients transplant options and hope for disease control with fewer complications. Several studies have attempted to assess the efficacy of RIC for treatment of high-risk ALL; however, most were small and the patient populations and treatment regimens were heterogeneous. In this study at the City of Hope, all patients received a Flu/Mel conditioning regimen and the stem cell source was PBSC. Despite the poor prognostic indicators and limited sample size, the 2-year OS and DFS of 61.5% for this patient population are encouraging. In comparison, the recent MRC/ECOG ALL Trial shows that standard risk ALL patients receiving allogeneic transplants have a 5-year OS of 62%, whereas the Philadelphia chromosome negative (Ph⁻) high-risk trial patients have an OS of 41% and Ph⁺ patient OS is only 22% [4].

The 21.5% NRM at 2 years compares very favorably with the International ALL Trial 2-year NRM of 35.8% for high-risk myeloablative transplant patients. The 2-year relapse rate of 21.1% was also similar to the 2-year rate of 25% from the International ALL Trial (interpolated from a 10-year graph) [4]. At 100 days NRM was 12.5%; however, an increase to 21.5% by 2 years posttransplant was attributable to cGVHD and associated infections.

Nearly all patients had GVHD to some extent (23 of 24 patients), and PBSCT is known to correlate with higher risk of GVHD [25]. The incidence of cGVHD was a cause of concern; however, in surviving patients, KPS scores were 80% to 100%, allowing a reasonably functional life after transplant. Jagasia finds that patients having cGVHD with any acute features have a poorer prognosis. In this group, half of the cGVHD cases had some acute features, only 2 of which were delayed acute presentation. There was no correlation between cGVHD with acute features and poor outcome. The low relapse rates in this study may be partially attributable to high GVHD; however, direct statistical tests were inconclusive because of patients numbers.

This study is consistent with the recent findings of Bachanova et al. [12] using CB for ALL RIC, whose 22-patient study is of similar size, high-risk patient composition and outcome. Both studies have a relatively low incidence of relapse (Stein and Forman [24] 2 years: 21%, Bachanova et al. [12] 3 years: 36%), especially for first remission patients after the second year. Although the stem cell sources and treatment details differ, both studies show significant improvement in OS compared to previously published data (Stein and Forman [24] 2 years: 61%, Bachanova et al. [12] 3 year: 50%).

Analysis of this data from 24 high-risk ALL patients did not find a significant association between age and survival; however, that is not unexpected given the skewed age distribution and sample size. Although younger patients might be expected to demonstrate significantly better outcomes in a larger, more age-diverse study, we demonstrate highly acceptable survival rates for older patients receiving RIC. Patients too old to be candidates for MA therapies may now be considered reasonable candidates for RIC PBSCT transplants. In this study, unrelated donor transplant patients had survival rates comparable to patients with related donors. A similar finding for unrelated donors is also recently reported for elderly patients in a large acute myelogenous leukemia (AML) transplant study (368 patients) [26] and in the recent CB ALL study [12]. For older patients, MUD transplant survivability is an important consideration, as the availability of eligible sibling donors diminishes with patient age.

Despite the high-risk nature of the patients in this study, all had low disease burden at the time of transplant, either in a complete remission or with low WBC and % blasts. Forty-two percent of patients were in CR1; however, no significant difference in outcome was detected for these patients compared to those beyond CR1. We are aware that this result is in contrast to the published literature and attribute this to the small sample size.

For adult Ph⁺ ALL patients, a safer alternative to standard allo-HCT is especially important. Historically, this population had a dismal survival rate of 10% to 20% when treated with standard chemotherapy alone 1, 14, 27. Use of imatinib mesylate and other tyrosine-kinase inhibitors is improving remission rates and durable responses, allowing for improved transplant [28] and nontransplant [29] survival. Despite this fact, allo-HCT is considered the only curative approach, and is the standard of care in CR1 for Ph⁺ ALL patients 27, 28, 30. Even though the presence of the Philadelphia chromosome was not part of the selection criteria for RIC in this study, 42% of patients were Ph⁺, reflecting the increased incidence of Philadelphia chromosome in older patients. Of the 10 Ph⁺ patients in this study, 5 have survived in remission, a DFS of 50% that is comparable to the DFS of Ph⁺ patients seen in a collaborative study by this group and Stanford (Ph⁺ DFS in CR1=48%, beyond CR1=26%) [31]. Because of increasing prevalence of Ph⁺ with increasing age 28, 32, the availability of effective reduced-intensity transplants is a crucial addition to the treatment armamentarium for these patients.

In conclusion, this retrospective study demonstrates optimistic survival rates for patients with high-risk ALL undergoing RIC, comparable to those seen in the literature for standard-risk patients undergoing myeloablative allo-HCT. These data also contribute to the body of evidence supporting a role for GVL in the treatment of ALL. Studies describing RIC transplant for ALL are scarce in the literature, and there are as yet no single-protocol prospective trials. Although our findings are exciting, the caveats of the retrospective nature of the study and its small sample size can be addressed only through future prospective trials in adults with ALL. To validate these findings and those of other studies, we plan to use this preliminary data as the basis of a proposal for a large phase II prospective clinical trial of reduced-intensity transplant in patients with high-risk ALL.

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Acknowledgments 

Financial disclosure: This study was supported in part by grants from the National Institutes of Health, CA30206 and CA33572. We would like to thank Karen Chang for hematopathology and Sean Wang for stem cell collection. We would like to acknowledge the dedicated nurses of the City of Hope Bone Marrow Transplant Unit for excellent care of our patients and support of medical research.

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Authorship 

Contribution: A.S.S. designed the original study, performed the research, analyzed the data and wrote the paper; J.M.P. and M.L.S. analyzed the data and critically reviewed the paper; N.M.K., R.T.S., N.C.T., K.C.S.W., and D.S. generated data; M.R.D. and D.S.S. critically reviewed the paper; S.H.T. analyzed the data and wrote the paper; and S.J.F. designed the original study and critically reviewed the paper.

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