Reader Responses: Would rituximab re-treatment help this patient with hemolytic anemia?

Here’s how readers responded to a You Make the Call question about treatment of Coombs-positive hemolytic anemia in a patient who declines to undergo splenectomy.


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There is no evidence that another treatment with rituximab will help. If he still refuses a splenectomy, other treatments can be considered.

Adel Z. Makary, MD
Danville, PA

Even though there is no information about the type of Coombs-positive hemolytic anemia this specific patient has, my therapeutic intervention would consist of first re-challenging with 4 weekly courses of low-dose rituximab (100 mg/m2 fixed dose), plus cyclophosphamide and dexamethasone. If there is no response to that, I would try cyclosporine. If still no response, then I would try eculizumab.

Spiros Chondropoulos, MD, PhD
Athens, Greece

No, I don’t think a second treatment with rituximab would be beneficial.

Colette Hanna, MD
Beirut, Lebanon

I suggest trying bortezomib, which our group used successfully for a 15 year-old boy with refractory Evans syndrome (see Knight T, et al. J Pediatr Hematol Oncol. 2018).

Yaddanapudi Ravindranath, MD
Detroit, MI

Rather than repeating rituximab, it would be better to try local splenic irradiation or a clinical trial with fostamatinib.

Mohamed Ali Latiweish, PhD
Benghazi, Libya

I doubt that rituximab, having failed once, would be useful the second time round. Had the patient responded to the first course of rituximab, the chances for a second response would be around 40%. As it is, with no response to the first course, chances of a good response to a second course are slim. I would consider adding in a steroid-sparing agent, probably mycophenolic acid, trying to keep the steroid dose down to a minimum. Depending on the response to mycophenolic acid, I would try to keep the splenectomy option open.

Aleksandar Mijovic, PhD
London, U.K.

Several questions ought to be asked:

  1. Is this a warm type or cold type autoimmune hemolytic anemia (AIHA)?
  2. Are there concomitant deficiencies? (e.g., iron deficiency due to chronic iron loss, fatty acid deficiency, etc.)
  3. How active is the hemolysis, as measured by lactate dehydrogenase levels over time?

If this was truly a rituximab-resistant warm type AIHA, it is unlikely that retreatment will be useful. If this is a cold type AIHA (cold agglutinin disease), I prefer using fludarabine in combination with rituximab.

In patients who have truly rituximab refractory AIHA (warm type), the prognosis in terms of response is poor. Splenectomy is considered similar to rituximab when considering short- and long-term efficacy, thus it would be the only recommendable option with a reasonable and known track record of safety and efficacy.

Beyond that, I would consider enrolling the patient in a clinical trial. There are several, some targeting complement and others targeting specific signaling pathways (SYK, etc.).

If a clinical trial is not available, results with other agents (cyclosporine, cyclophosphamide, mycophenolic acid, danazol) are based on smaller series and may vary.

Julio Hajdenberg, MD
Orlando, FL

There is evidence that a second course of rituximab doesn’t work in chronic immune thrombocytopenic purpura (ITP) if it fails to work the first time, so I would not recommend that here.

Edwin N. Forman, MD
New York, NY

Yes, rituximab is likely to benefit.

Tarun K. Dutta, MD
Puducherry, India

I see a much lower response rate to rituximab in AIHA than in ITP. Therefore, I would not try it a second time, assuming that this patient has warm-reacting autoantibody hemolytic anemia, not cold-reacting. This information is not specified in the history.

For this patient, I would start a secondline drug, preferably mycophenolic acid, for immunosuppression. It is very well tolerated at 1,000 mg twice daily, even in elderly patients (which this patient is not). Since low-dose prednisone is not keeping his hemoglobin at a satisfactory level, I would expect to achieve a higher hemoglobin (at least 9-10 g/dL) before tapering the prednisone further.

Marilyn J. Telen, MD
Durham, NC

I would consider the effect of prednisone and a hemoglobin level of 7 g/dL as insufficient here, and prednisone in the long run would prove to be too toxic. A second treatment with rituximab is unlikely to help. I would try ciclosporin.

Clemens B. Caspar, MD
Baden, Switzerland

AIHA that is refractory to corticosteroid and rituximab may be from a common variable immunodeficiency (CVID), so I would get a quantitative immunoglobulin determination to assess for CVID.  If hypogammaglobulinemia is present, the anemia may respond to intravenous immunoglobulin therapy.

Emmanuel Besa, MD
Philadelphia, PA

It is unlikely that repeating rituximab would work, given that apparently nothing has changed after the first attempt with rituximab (see Hasan, et al. Am. J. Hematol. 2009). However, combining rituximab with other treatments might be very useful: dexamethasone, bortezomib, or experimental approaches (e.g., an SYK inhibitor, a FcRn blocker, or even a complement inhibitor).

James B. Bussel, MD (James)
New York, NY

I would treat with mycophenolate mofetil instead of another round of rituximab.

John J. Strouse, MD, PhD
Durham, NC

Does this patient have complement bound to his red cells? If so, another option to consider would be complement inhibition (eculizumab), since rituximab has failed. Another option might be daratumumab, which a few hematologists have had success with in autoimmune disorders.

Neil Blumberg, MD
Rochester, NY

He may respond to repeat rituximab, but I would try to convince him to get the splenectomy.

Shakila Khan, MD (Shakila)
Rochester, MN