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Hematology 2022: Nonmalignant diseases

CME

Key Studies in Nonmalignant Hematology: Independent Conference Coverage of ASH 2022

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: March 23, 2023

Expiration: March 22, 2024

Catherine M. Broome
Catherine M. Broome, MD
Corey Cutler
Corey Cutler, MD, MPH, FRCPC
David Dingli
David Dingli, MD, PhD
Marshall Mazepa
Marshall Mazepa, MD
Allison P Wheeler
Allison P Wheeler, MD, MSCI
CME/CE Information

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CAD: Background

Catherine M. Broome, MD:
CAD is a rare type of chronic autoimmune hemolytic anemia.3 CAD accounts for approximately 15% to 20% of all autoimmune hemolytic anemias, and we know that hemolysis in this disease is mediated by activation of the classical complement pathway. We also know that, in addition to symptoms of anemia, fatigue, and hemoglobinuria, CAD may negatively affect quality of life (QoL) for patients.4

PROs From Phase III CADENZA Study of Sutimlimab vs Placebo in Patients With CAD: Study Design

Catherine M. Broome, MD:
CADENZA was a randomized, double-blind phase III trial evaluating sutimlimab, a selective classical complement pathway inhibitor, vs placebo in patients with CAD and no recent history of transfusion (NCT03347422). The study consisted of 2 parts: Part A was a 26-week double-blind treatment period, and part B was an open-label safety extension period. 

In a previous report from part A, the study had met its primary endpoint. Sutimlimab was shown to rapidly halt hemolysis, increase hemoglobin levels, and improve fatigue in patients with CAD.5

At ASH 2022, data were presented for part B evaluating long-term patient-reported outcomes (PROs) for patients who received sutimlimab, including those who received placebo in part A and then switched to sutimlimab in the open-label extension.6

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CADENZA PRO Analysis: Measures and Baseline Characteristics

Catherine M. Broome, MD:
Of 42 patients enrolled on part A, 39 (93%) completed part A and entered part B, and 32 of the 39 (82%) completed part B. The median duration of sutimlimab treatment in part B was approximately 99 weeks (range: 22-177). As we might expect for patients with CAD, the average age for patients on the study was 67 years (range: 46-88). Slightly fewer than 80% of these patients were female, which is not uncommon for an autoimmune disease. The baseline mean Functional Assessment of Chronic Illness Therapy―Fatigue (FACIT-Fatigue) score of 33.0 (standard deviation: 11.2) was in line with those of patients with other serious illnesses.

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CADENZA PRO Analysis: Hematologic Response

Catherine M. Broome, MD:
As previously stated, in part A, a significant improvement in hemoglobin levels was seen in patients receiving sutimlimab vs placebo at 26 weeks. Patients receiving placebo in part A saw the same increase in hemoglobin when receiving active drug in part B. Similarly, bilirubin levels―which are a very sensitive indicator of extravascular hemolysis―also improved significantly in patients who were receiving active drug, and patients who were receiving placebo saw the same benefit once they crossed over to active treatment in part B.

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CADENZA PRO Analysis: Changes in FACIT-Fatigue Score

Catherine M. Broome, MD:
Improvements in laboratory values are important, but so are improvements in QoL for this patient population. Thus, this study also looked at fatigue using FACIT-Fatigue, a 13-item instrument that assesses fatigue and its impact on activities of daily living. Patients who were receiving sutimlimab―and therefore had their classical complement pathway activation controlled―experienced a mean improvement in FACIT-Fatigue scores of 8.8 points (standard error: 2.1) at their last on-treatment visit. In addition, this study demonstrated that patients who had been receiving placebo and then switched to active drug had an improvement in FACIT-Fatigue scores (mean change: 8.0 points; standard error: 2.8), and those results were maintained throughout the duration of the open-label extension study.

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CADENZA PRO Analysis: Patient Fatigue (PGIS) and Overall QoL (PGIC)

Catherine M. Broome, MD:
When patient fatigue (Patient Global Impression of Severity scale) and overall QoL (Patient Global Impression of Change scale) were examined, all patients receiving sutimlimab exhibited significantly decreased fatigue, with the majority of patients reporting either no or mild fatigue at Week 87 (78% vs 47% at baseline). The majority of patients (71%) also reported improvement in overall QoL by Week 87. Furthermore, these responses were maintained throughout the duration of the open-label extension of this trial.

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CADENZA PRO: SF-12 PCS and MCS

Catherine M. Broome, MD:
Improvements in Physical Component Score and Mental Component Score also were seen with long-term sutimlimab. Patients achieved significant improvements in their physical (mean change: 4.9; standard error: 1.7) and mental (mean change: 4.0; standard error: 1.8) component scores at last on-treatment visit, and this benefit also was seen in those who were switched from placebo to active treatment with sutimlimab.

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CADENZA PRO: EQ VAS

Catherine M. Broome, MD:
Rapid improvement in EuroQol Visual Analog Scale also was seen in patients randomized to receive sutimlimab and those crossing over from placebo to sutimlimab treatment. The mean change for all patients at last on-treatment visit was 15.3 points (standard error: 3.7).

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CADENZA PRO Analysis: Conclusions and Implications

Catherine M. Broome, MD:
This clinical trial demonstrated that continued inhibition of the classical complement pathway with sutimlimab resulted not only in laboratory benefits, but also in meaningful long-term benefits in fatigue and other patient-reported QoL measures.

This study was an excellent demonstration of the immediate benefits of classical complement pathway inhibition and the ability of those benefits to persist through long-term treatment in patients with CAD. For instance, hemoglobin and QoL both remained improved based on decreasing classical complement pathway activity.

The patients on this trial realistically recapitulate real-world patients we see in our clinic. All of the patients in this clinical trial had not received prior blood transfusions and had mild to moderate decreases in hemoglobin―so these were not severely affected patients, and yet a marked benefit was seen in their QoL by inhibiting classical complement pathway activity with sutimlimab.

As we are watching and managing our patients with CAD, we should be mindful that even in patients who seem to have minor anemia, QoL is likely being affected by the disease. We may want to consider discussing sutimlimab therapy with all of our patients with CAD so that they can gain access to these QoL improvement benefits.

At this time, it is unclear whether all healthcare professionals (HCPs) are asking patients with CAD if they are experiencing fatigue, but I think it is important to ask things like: “Are you able to do the things that you enjoy? Are you able to get all of your housework done? Are you able to cook your own meals? How many hours a day are you sleeping? How many hours a day are you sitting in a chair?” Those kinds of questions will give a sense of how significantly affected your patients’ daily life might be regarding their disease. If you find that a patient has substantially modified their daily life to accommodate disease symptoms, that patient might be one for whom consideration of therapy with sutimlimab would be particularly important

Your patient with CAD mentions that she is experiencing fatigue and has had low hemoglobin (≤10 g/dL) in her previous 2 laboratory assessments. At ASH 2022, data were presented from the phase III CADENZA study of sutimlimab, a selective classical complement pathway inhibitor, vs placebo in patients with CAD and no recent history of transfusion. The study included analyses evaluating the role of sutimlimab on patients’ fatigue and other quality of life measures, with the goal of expanding treatment options for patients with the disease. As part of your recommendation to try out this new treatment, you would mention to her that all of these results were reported for the CADENZA study EXCEPT which one?

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