Revisiting the non‐transfusion‐dependent (NTDT) vs. transfusion‐dependent (TDT) thalassemia classification 10 years later

Clinical classification of patients with thalassemia is the key to making management and follow up decisions. Patients were commonly classified as having a thalassemia major, intermedia or minor phenotype based on clinical presentation and genotype correlates. Around 10 years ago, we recommended the introduction of an alternate classification system / terminology for clinically relevant forms of thalassemia (excluding thalassemia carriers and minor/trait patients) based on transfusion requirements, since receipt of transfusions in this chronic disease modulates the underlying pathophysiology and informs management needs.1, 2 The terms non-transfusion-dependent (NTDT) and transfusion-dependent (TDT) thalassemia were introduced and are now widely applied in clinical practice and research; including recent international management guidelines and eligibility criteria for clinical trials with novel therapies.3, 4 We do recognize, however, that some confusion remains with regards to the background and implications of using such classification. In our original recommendation, primarily based on expert opinion, we had intended to restrict the use of the term TDT to those patients who are “dependent” on transfusions for survival. These are usually patients with a thalassemia major phenotype, characterized by early presentation to clinical care with severe anemia that prompts physicians to initiate regular and lifelong transfusions. The mainstay of care in these patients is a tailored transfusion program that maintains pre-transfusion hemoglobin levels between 9-10 g/dL, with adequate management of secondary iron overload. The NTDT patients were defined as those who are not dependent on transfusions for survival, including thalassemia intermedia patients with clinical presentation opposite to that aforementioned for TDT. We did caution, however, that these patients may still require transfusions at the discretion of the treating physician either occasionally, when acute or subacute drops of hemoglobin levels are anticipated (eg, during surgery, pregnancy, or infections); or even frequently - yet for defined and short periods of time - to improve the underlying anemia which may be negatively impacting growth and development in children or causing clinical morbidity in adults. The concern with iron overload in NTDT patients is attributed to increased intestinal absorption stemming from ineffective erythropoiesis. The NTDT/TDT classification may be straightforward when looking at the historic and global picture of an individual patient but may become subject to various interpretations when considered cross-sectionally or during narrow time windows in later stages of the disease. This becomes even more challenging considering changes in the underlying pathology overtime especially those induced by novel therapies. Therefore, we would like to highlight two main scenarios that we believe our colleagues may be puzzled with (Figure 1). As mentioned earlier, one may encounter NTDT patients that are actually receiving frequent and even regular transfusions during a specific period of time. Ideally, these patients should not be labeled as TDT, as the latter is designed to reflect the underlying severity of disease since diagnosis and implies long-term (past) and lifelong (future) exposure to iron overload and chelation therapy with associated implications in various organs. One exception to this may be in patients who now became definitively dependent on transfusions for the remainder of their disease. In this special scenario, patients may be classified as TDT and managed as such, but with additional designation to clarify that this is a new transformation compared to patients who have had TDT since diagnosis. For this purpose, we recommend the use of the term neoTDT. That said, there are few important questions to ask on frequently transfused NTDT which are directly related to the objective of management. Should patients be treated based on NTDT or TDT guidelines and prescribing information for iron chelation therapy? Iron chelation decisions are based on baseline iron overload status and ongoing iron intake, as well as functional status of vital organs from a safety standpoint. Other historic attributes of the disease are less relevant in this setting, and the patient status at the time of iron chelation decision should inform choices. Levels of systemic, hepatic, and/or cardiac iron indices at “baseline” and the rate of transfusion therapy and subsequent iron intake in the past 6 months should be taken into consideration to decide on the choice and dose of iron chelator; while taking into consideration relevant organ function measures for the liver, kidney, and heart. Since regular transfusion therapy is often temporary in this group of patients, iron chelation decisions should be revisited every time there is a considerable change in transfusion requirement. Another important question is whether these patients should be included in clinical trials of novel therapies designed for NTDT or TDT patients. The answer to this question is trickier. In our opinion, since the goal for most novel therapies is to modify the disease or its management (transfusion) needs permanently, or over an extended period of time, patient eligibility should rely on a long rather than short period of historic observation prior to trial inclusion. For instance, the concern here is that an NTDT patient on regular transfusions for the last 3-6 months to treat an extramedullary hematopoietic tumor, who was anyhow meant to discontinue transfusions shortly after tumor response, would end up being included in a TDT trial aiming to reduce transfusion requirement. Although most ongoing clinical trials only look at the patient's transfusion requirement in the last 6 months prior to enrollment to define NTDT vs TDT status (commonly using cut-offs of 4-6 blood units), there are usually additional eligibility criteria that allow better assessment of the patients underlying phenotype since diagnosis. Terminology put aside, investigators should also exercise their own judgment on whether patients are suitable or not for a specific trial, by looking back at how long the patient has been on regular transfusions or expected to be in the future. If this exceeds a year in either direction, then this patient should probably be considered for therapies aiming to reduce transfusion requirement; although we recommend retaining the terminology of frequently transfused NTDT rather than TDT for the aforementioned reasons. Lastly, although these patients may not be eligible for NTDT trials targeting hemoglobin level, they may be considered in the future once their regular transfusion therapy is tapered or discontinued. Our key message here is that patients need to be in a relatively “steady-state” before any such management or research decisions are made. Novel therapies for TDT mainly target transfusion requirement aiming for reduction or independence. This leads to a scenario opposite to that mentioned earlier for NTDT. The key question here is whether responding patients to such therapies should be reclassified to NTDT. The short answer is “no”. If patients received curative therapy and the disease was permanently and fundamentally modified leading to sustained transfusion independence, they should be classified as exTDT; such may be the case with gene therapy or editing and bone marrow transplantation. Patients who only achieved reduction in their transfusion requirement should be labeled as intermittently transfused TDT (itTDT), and considerations for iron chelation therapy and further inclusion in novel therapy trials should follow the same rationale mentioned above for frequently transfused NTDT. The underlying molecular profile of TDT patients also remains relevant in considerations of novel therapies targeting transfusion requirement. The genetic heterogeneity of TDT implies that some patients may carry mutations or modifiers associated with very low red blood cell (RBC) synthesis, while others with higher numbers of RBCs (although insufficient to be considered NTDT). Regular transfusion therapy may mask these differences due to the intrinsic ability of blood transfusion to suppress endogenous erythropoiesis.5 Therefore, the hemoglobin levels these patients are able to produce with new treatments may reflect a combination of the intrinsic ability of each patient to produce RBCs in the absence of intervention as well as the ability of the drug itself to increase hemoglobin levels. Thus, clinicians and investigators should not only rely on a TDT classification but also consider the ability of individual patients to produce RBCs based on the genetic profile during management decisions on novel therapies. Despite its close association with a diagnosis of thalassemia, transfusion therapy remains an intervention that is not only driven by underlying disease severity but also physician choices, which leaves room for considerable variability in practices at the regional and international levels. Clinical classification in thalassemia should remain individualized and rely on evidence from laboratory and clinical observations throughout the patient journey. We hope that our modified recommendations can help classify patients based on historic and evolving transfusion needs to help tailor care and research. K.M.M. has been or is a consultant for Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics and Vifor Pharma. M.D.C. has been or is a consultant for Novartis, Celgene Corp (Bristol Myers Squibb), Vifor Pharma and Ionis Pharmaceuticals; and received research funding from Novartis, Celgene Corp (Bristol Myers Squibb), La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics and CRISPR Therapeutics. V.V. has been or is a consultant for Agios Pharmaceuticals, Celgene Corp (Bristol Myers Squibb), Roche, Novartis and Protagonist Therapeutics; and received research funding from Agios Pharmaceuticals, Celgene Corp (Bristol Myers Squibb), Roche, Novartis and Protagonist Therapeutics. AK. has been or is a consultant for Celgene Corp (Bristol Myers Squibb), Novartis, Apopharma/Chiesi Farmaceutici, Vifor Pharma, Ionis Pharmaceuticals, Agios Pharmaceuticals, CRISPR Therapeutics/Vertex Pharmaceuticals and Gilead; and received research funding from Novartis. S.R. is a member of the scientific advisory board of Ionis Pharmaceuticals, Meira GTx, Incyte and Disc Medicine and owns stock options from Disc Medicine and Meira GTx. He has been or is consultant for Cambridge Healthcare Res, Celgene Corp (Bristol Myers Squibb), Catenion, First Manhattan Co., FORMA Therapeutics, Ghost Tree Capital, Keros Therapeutics, Noble insight, Protagonist Therapeutics, Sanofi Aventis U.S., Slingshot Insight, Techspert.io and BVF Partners L.P., Rallybio LLC and venBio Select LLC. A.T.T. has been or is consultant for Novartis, Celgene Corp (Bristol Myers Squibb), Vifor Pharma, Silence Therapeutics and Ionis Pharmaceuticals; and received research funding from Novartis, Celgene Corp (Bristol Myers Squibb), La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics and Agios Pharmaceuticals. All authors contributed to manuscript drafting or critical review and final approval for submission. None. No data in the manuscript.