Estimating prognosis in sickle cell anemia (SCA) assumes greater importance as intensive treatments, such as hematopoietic SCT (HSCT), are being tested. Here we estimate the mortality risk from the walk-PHaSST (Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease) trial of homozygous SCA patients with suspected pulmonary hypertension (19/468 deaths; 10 centers in the US and UK). Parallel investigations were also undertaken in the Cooperative Study of Sickle Cell Disease (CSCCD) and a contemporary urban sickle cell disease population (Case Western Reserve University-University Hospitals (CWRU-UH), Cleveland, OH, USA). One- and two-value positive predictive values for 2-year mortality (from study entry) are calculated using factors that include demographics, laboratory values and clinical evaluations. We define high-, intermediate-, and low-risk SCA as >15%, 10–15% and <10% 2-year mortality. In walk-PHaSST, no single factor qualifies as high-risk SCA, although several combinations of two factors (that is, both age >35 years and history of chronic transfusion) do. Either elevated white blood cell count (>13.5 × 103 cells/mcL, 7/70 deaths) or elevated Tricuspid Regurgitant Jet Velocity (⩾3.0 m/s, 8/67 deaths) was individually associated with intermediate-risk disease, as were many two-factor combinations. N-terminal pro-brain natriuretic peptide >160 ng/L, lactate dehydrogenase >600 IU/L, history of chronic transfusion, sepsis or age >35 years are individually associated with low-risk SCA, as are many two-factor combinations. SCA risk was integrated with estimated donor type-associated risk from HSCT to form 'Traffic Light' eligibility criteria for clinical trials of HSCT. This method is adaptable to evolutions in clinical care.
Sickle cell anemia (SCA) is one of the most common monogenic disorders in the world. SCA affects approximately 100 000 Americans and 1 in 400–700 African-American newborns.1 Homozygous Hb S HbSS confers significant morbidity during childhood and risk for mortality during early and mid-adult life. Allogeneic hematopoietic SCT (HSCT) is the only known curative treatment for SCA. However, timing of and acceptable risk from HSCT in this chronic non-malignant disease is a matter for active debate.
In 1984, the first successful myeloablative allogeneic HSCT was performed in a child who had concurrent SCA and AML.2 This resulted in a cure of both conditions. Since then, myeloablative HSCT has been performed in hundreds of children with SCA, with steadily improving results. In one large subset of transplanted subjects, the OS and EFS were 100% and 95%, respectively.3 Adults with SCA were not widely regarded as transplant candidates, owing to the clinical heterogeneity of prognosis and cumulative organ damage. To address this, reduced intensity or non-myeloablative preparative regimens for HSCT have recently been attempted in this population. At the National Institutes of Health (NIH), 26/30 SCA adults had long-term donor engraftment following a non-myeloablative preparative regimen and matched sibling donor (MSD) transplant.4 However, acceptable MSDs are available in <20% of patients,5, 6 whereas haploidentical donors may be available in >75% of adults with SCA.7 Bolaños-Meade et al.7 at Johns Hopkins University reported on 14 adults who underwent a reduced intensity preparative regimen, followed by a haploidentical graft. At a median of 2 years post transplant, all patients were alive, and 8/14 had engrafted successfully. Therefore, most adult SCA patients have a potential stem cell donor, in the context of a clinical trial, if HSCT is clinically indicated.
In SCA, alternate donor HSCT could be offered in clinical trials to the sickest patients, in whom the risk of transplant-related morbidity and mortality is counterbalanced by risk from the disease itself. Further, patients with SCA are uniformly surviving childhood,8 which enlarges the population that could benefit from successful transplantation as adults. There is a consensus that HSCT via clinical trial should be offered to adult SCA subjects who have a poor prognosis despite maximal medical therapy, although the definition of ‘poor prognosis’ remains imprecise.9, 10, 11 In 2011, investigators at the NIH published eligibility criteria that served as the basis for non-myeloablative MSD transplant in adults with SCA.12 Subsequently, Krishnamurti13 published more conservative criteria for the MSD and matched unrelated donor (MUD) trial: ‘Bone Marrow Transplantation in Young Adults with Severe Sickle Cell Disease’ (STRIDE, Table 1). Neither guideline is based on calculated mortality risk.
In ‘Traffic Light’ eligibility, we seek to integrate mortality risk from SCA, calculated from observational studies in adults, with estimated risk from HSCT donor source. We propose that this flexible schema can guide future eligibility for clinical trials of HSCT in adults with SCA, while serving as a framework for risk–benefit discussions with patients and families.
Subjects and methods
We examined adult patients with phenotypic HbSS from the Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease (walk-PHaSST trial),14, 15 the Cooperative Study of Sickle Cell Disease (CSSCD),16 and the Case Western Reserve University-University Hospitals (CWRU-UH) Sickle Cell Disease clinic database.
Walk-PHaSST (open from 2007 to 2009) included patients from nine centers in the United States and one center in the United Kingdom. Of the 468 adult HbSS patients who entered into the screening study, 74 were randomized into the treatment study and received either sildenafil or placebo to determine whether exercise capacity could be increased. Randomized subjects had shown a decreased exercise capacity and an abnormal tricuspid regurgitant jet velocity (TRV) by echocardiographic examinations at screening.17 An estimated pulmonary arterial systolic pressure was considered elevated if the TRV was ⩾2.7 m/s. Our report includes data obtained at study entry, prior to randomization for treatment, from the entire HbSS population (n=468). Of note, the Walk-PHaSST observational population may be enriched with older (mean age 36.6±11.9 years) higher-risk patients, since the goal of the study was to identify subjects with a high TRV who would be eligible for the main interventional trial. There were 19 deaths over 2 years. The demographic details of these patients are published separately.14
The Cooperative Study of Sickle Cell Disease (CSCCD; open from 1979 to 1988) was an NIH-funded observational study that gathered demographic, medical history, physical examination, routine lab and mortality data on 708 adults with phenotypic homozygous HbSS, recruited at 23 centers in the United States. There was no bias for screening, although most sites were pediatric, and the adult population was younger (27.5±8.2 years). Hydroxyurea, the mainstay of current disease management in homozygous SCA, was not widely available during the CSCCD era. Of the 708 adult patients, 652 had long-term follow-up, with 59 deaths over 3 years.
At CWRU-UH, adult HbSS and HbS-β-thalassemia patients on whom we had sufficient data were analyzed retrospectively (n=122, with a mean age of 32.6±12.2 years). Three deaths (2.5% of patients) in homozygous adults occurred over 2 years. The University Hospitals Case Medical Center Institutional Review Board approved this study.
Markers of disease severity
We analyzed markers of disease severity, previously shown to confer mortality risk in SCA, for their prognostic value in walk-PHaSST and in CSSCD. These included results of echocardiographic examinations17, 18, 19 perfomed >2 weeks from vaso-occlusive crisis (VOC) or acute chest syndrome, and blood and urine analyses obtained at clinical baseline (N-terminal pro-brain natriuretic peptide (NT-proBNP),20, 21 lactate dehydrogenase (LDH),22 WBC,16 albuminuria23), as well as demographics and medical history (age, gender, history of sepsis, of stroke, of acute chest syndrome16 or of iron overload).24 We also asked whether a Bayesian Network Model (BNM), derived from the CSSCD data, estimated prognosis in walk-PHaSST. The BNM incorporates 25 historical clinical events and laboratory results to estimate SCA mortality risk.25
Data collection and definitions
Well-annotated demographic, historical, clinical and laboratory data were available from both walk-PHaSST and CSSCD, as defined in each study.14, 16 At CWRU-UH, data were collected from medical records at clinical baseline, that is, >2 weeks from a clinically significant VOC. The number of significant annual VOC was determined by discharge summaries averaged over a 5-year period. Sickle hepatopathy, which is a clinical diagnosis,26 was identified in the CWRU-UH population in five patients who had a persistent elevation in alanine transaminase or direct bilirubin, in the appropriate clinical setting. Estimated glomerular filtration rate was calculated using the ‘Modification of Diet in Renal Disease’ four-variable equation.27 ‘Chronic transfusions’ were defined as scheduled simple transfusion, exchange transfusion or serial HbA measurements >30% (in non-HbS-β-thalassemia) on >50% of annual Hb analyses from the previous year. We operationally defined chronic transfusions as >12 annual packed red cell transfusions, the majority given non-urgently. An ‘at-risk’ TRV was ⩾3.0 m/s, previously reported as a strong predictor of mortality,28 and an ‘at-risk’ serum NT-proBNP level was >160 ng/L.20 By convention, macroalbuminuria is >300 mg of urinary albumin per g creatinine (mg/g). The BNM severity score was calculated using an on-line Java-enabled program, as per Sebastiani et al.25, 29, in which elevated age was >35 years, an elevated LDH was >600 IU/L and an elevated WBC was >13.5 × 103 cells/μL. A BNM Severity score of >0.95 ‘units’ (range 0 to 1) was considered high risk in our analysis.
Positive predictive values (PPVs)
Single-variable PPVs for short-term mortality were calculated from markers of disease severity in walk-PHaSST and in CSSCD, by taking the number of patients in a risk group who died divided by the total number of patients in that risk group. For example, to calculate a single-variable PPV for WBC count in walk-PHaSST, the total number of subjects with an elevated WBC at study entry is the denominator (n=70), while the subset with an elevated WBC who died is the numerator (7/70 or 10%). Combinations of two variables are used to calculate two-variable PPVs in walk-PHaSST if each variable alone confers ⩾5% mortality risk, such as a WBC>13.5 × 103 cells × 103/μL and TRV⩾3.0 m/s (Figure 1). Here the number of subjects with both an elevated WBC and an elevated TRV at study entry who subsequently died (n=3) is divided by the total number of subjects with both abnormalities at study entry (n=13 or 3/13, 23%). BNM severity score ⩾0.95 was incorporated into a two-variable PPV calculations from walk-PHaSST only with TRV and NT-proBNP, as other markers of disease severity were integral to the BNM score itself. Data limitations in CSCCD (for example, no TRV) allow only single-variable PPV calculations from those data. High-level morbidity from SCA, such as recurrent VOC episodes, recurrent ACS or stroke, was also included in Traffic Light guidelines.
Donor risk assessment
The greatest HSCT experience in SCA to date is in myeloablative transplant,3, 30, 31 and these are mostly MSD transplants in children. At present, we stratify haploidentical transplants more stringently than MSD owing to the high risk of graft loss. Because of limited data in adults with SCA and because of published reports of patient concerns regarding GVHD in SCA,32, 33, 34 we have stratified MUD apart from MSD despite promising data in other conditions, as MUD transplants have been associated with increased chronic GVHD.35 Further, unlike other Hb gene disorders such as beta-thalassemia,10 there is limited real-world availability of MUDs in SCA. Published experience in adults with SCA to date primarily has been of MSD or haploidentical donor transplants utilizing reduced intensity preparatory regimens.
Traffic Light eligibility for HSCT
Given that published studies in adults overwhelmingly report non-myeloablative strategies, our model assumes that paradigm for risk estimates.4, 5, 7 Weighted Traffic Light eligibility guidelines for clinical trial of HSCT in SCA (Table 2) are conceptualized as: Red Light, ‘Stop and evaluate’—Patients with low risk SCA would be offered only low-risk MSD transplants, which have demonstrated long-term safety and efficacy in both children and adults.3, 12, 30, 31 Yellow Light, ‘Proceed with caution’—Patients with intermediate risk SCA, absent an appropriate MSD, could also be offered HSCT on trial from moderate-risk alternate donors (MUD or haploidentical) that have demonstrated safety and efficacy in adults with SCA or in parallel clinical conditions.7, 11, 13, 36 Green Light, ‘Go’—Patients with highest-risk SCA would be offered HSCT on trial from any available donor (MSD, MUD or haploidentical or cord blood SCT, in that order). Cord blood transplant, with moderate efficacy and safety in children with SCA, may limit the risk of GVHD but has not been widely studied in adults.37 At any SCA risk, subjects would be offered the lowest-risk donor that is available to them. Low-risk SCA is defined as morbid disease and 5–10% estimated short-term mortality and morbid disease, and intermediate risk is highly morbid SCA or 10–15% estimated short-term mortality, while high-risk is >15% estimated short-term mortality.
Transplant evaluation in the CWRU-UH population
Traffic Light eligibility for HSCT was assessed in the adult HbSS population at CWRU-UH, and its distribution was calculated. We reviewed the three deaths that occurred over 2 years at our institution and determined their Traffic Light prognostic category in retrospect.
Positive predictive value calculations
Using mortality data from walk-PHaSST, we arbitrarily established three risk stratifications (>15%, 10–15% and 5-10%) 2-year mortality based on one- or two-variable PPV mortality calculations (Table 3a and b), compared with overall 2-year mortality of 4.0% (19 of 468). These data form the basis for the disease severity in Traffic Light (Table 2).
No single-variable PPV identified high-risk SCA, though several combinations of two factors (that is, both age >35 years and history of chronic transfusion) did. Both elevated WBC count (7/70 deaths) and elevated TRV (8/67 deaths) were individually associated with intermediate risk disease, as were many two-factor combinations. NT-proBNP, LDH, history of chronic transfusion, sepsis or age >35 years were individually associated with low-risk SCA, as were many two-factor combinations. We did not find substantial (>5%) risk of short-term mortality associated with a history of VOC, acute chest or stroke, and thus these risk factors were not included in Table 3a. In determining the final criteria for the Traffic Light, risk from BNM was omitted as it required significantly more data to compute the other risk factors, making it challenging to use in a clinical setting.
We then tested these risk calculations in the CSSCD data for NT-proBNP, WB count, LDH, and age (Table 3c). Subjects evaluated in CSSCD (assembled more than two decades before walk-PHaSST) had an overall 3-year mortality of 9.0% (59/652). Calculated PPVs for NT-proBNP WBC count, LDH, and age were directionally similar between studies but varied in the comparative risk they appear to confer (see Table 3a and c).
Transplant evaluation in the CWRU-UH population
Most patients had at least one indication for transplant on trial according to the NIH criteria (86.1%; 149 of 173) of CWRU-UH Subjects, which did not exclude patients with HbSC. In all, 122/173 (70.5%) of CWRU-UH patients had phenotypic HbSS or HbS-β-thalassemia, which is a prerequisite for inclusion in the STRIDE trial (ClinicalTrials.gov Identifier: NCT01565616). Of these, 75.4% (92/122) SCA patients, or 53% (92/173) of the entire population, had at least one indication for transplant in the STRIDE trial (using MSD or MUD, Table 1). By Traffic Light eligibility guidelines, 15/122 (12%) of the CWRU-UH HbSS population had low-risk (red light) disease and would be offered only MSD transplant, 64/122 (54%) had intermediate-risk (yellow light) disease and could also be offered haploidentical or MUD transplant and 28/122 (23%) had high-risk (green light) disease and could be offered any available donor type on study, including cord blood (Figure 2). Fifteen of the 122 (12%) SCA patients had no indication for HSCT, as they did not have ‘morbid disease’. We retrospectively examined disease risk in three SCA patients who died at our center over 24 months. Two patient were intermediate risk (TRV⩾3.0 m/s and highly morbid disease due to estimated glomerular filtration rate of 60 ml/min, respectively) and one patient was high risk (both NT-proBNP>160 ng/L and WBC>13.5 × 103 cells/μL).
Here we propose eligibility for trials of HSCT in adults with SCA using readily available baseline clinical characteristics (demographic, medical history, imaging and laboratory evaluation) from previously assembled clinical trials in sickle cell disease. CSSCD is the largest study of adults with SCA, and walk-PHaSST better represents the present adult SCA population in the United States and United Kingdom. In both of these observational studies, cardiovascular perturbation (elevated TRV, elevated NT-proBNP) and inflammation (elevated WBC count), together or alone, were significant markers of disease risk in adults with SCA.
Our goal was to marry available prognostic data for mortality in SCA to estimates of risk from HSCT. However, our analysis was confined to the adult SCA population and the risk factors identified may not be valid in a pediatric population. In addition, potential prognostic data were missing (thrombosis history)38 or incomplete (albuminuria), and subjects were followed up only for 2 or 3 years. Therefore, based on our current data, we cannot predict intermediate mortality risk (that is, 5 or 10 years) or its impact on decisions about transplant.
Risk–benefit analyses in HSCT, whenever possible, should be based on estimates of risks to the patient’s life from the sickle cell anemia itself, given the potential for life-threatening complications from HSCT in a non-malignant condition. It is notable that several clinical values (history of acute chest, stroke, VOC) that were predictive in the past did not associate with substantial (>5%) short-term mortality in the walk-PHaSST trial. It is unclear if this represents a lack of power of the study or a change in disease management in the modern era. Symptoms and clinical history may assume equivalence to or prognostic primacy over objective laboratory findings and tests as larger and more detailed observational databases emerge in future to inform these critical decisions.
We recommend that all evaluations for transplant only be undertaken in patients who have been optimally treated for SCA, whether with hydroxyurea or transfusions. Nonetheless, when applied to contemporary evaluable homozygous SCA subjects (CWRU-UH), 75% of subjects fulfilled Traffic Light eligibility for moderate- or high-risk HSCT based on short-term mortality risk and/or highly morbid disease. Given the growing feasibility of haploidentical HSCT, we estimate that the majority of our adult HbSS population would be eligible for HSCT clinical trials and would have an available donor.7 Going forward, improvements in HSCT technique may further drive the risk–benefit ratio in favor of transplanting patients at lower risk from SCA. Traffic Light criteria could then be adapted to reflect this change in practice. Of note, risk–benefit for HSCT in non-homozygous sickle cell disease awaits clarification and is not addressed in this study.
It will be important to assess additional risk factors in a prospective manner (as begun at our institution), so that more accurate risk stratification for HSCT can be developed in the future. Although criteria applied for HSCT eligibility are likely to be different from those used for other therapeutic studies in SCA, informed decisions by patients, their families and their health-care team about emerging higher-risk non-HSCT treatment strategies in future may benefit from better prognostic indicators. Indeed, the need for database development, to assess and follow evolving mortality risk in sickle cell disease, may be one of the most important messages of our study.
Weighted Traffic Light eligibility integrates morbidity and short-term mortality risk from SCA, based on best available current data, with risk estimates for conventional and alternative allogeneic donors in HSCT. These guidelines should facilitate appropriate patient selection and improve risk–benefit counseling for clinical trials of HSCT in SCA. Further, this schema is flexible and amenable to modification. This is important, as risk calculations in SCA and for HSCT are sure to evolve in the modern era. Traffic Light eligibility guidelines represent a significantly improved tool in guiding decisions about HSCT for adults with SCA.
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Dr Gladwin reports the following conflict of interest. Bayer Pharma AG: consultancy and research funding; US Government: co-inventor on a provisional patent for nitrite salts for cardiovascular indications. The other authors declare no conflict of interest.
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