Here’s how readers responded to a You Make the Call question about a patient with CLL who developed warm autoimmune hemolytic anemia.
Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.
I would increase the prednisone to 1 mg/kg while starting ibrutinib, assuming there is no contraindication to using that drug in this patient. If there is a response, I would then slowly taper prednisone over six weeks and continue on ibrutinib as a single agent. Might also consider rituximab in addition if response is delayed.
Paul Rosenthal, MD
Berkshire Medical Center
Measure the patient’s immunoglobulin levels. This Rai stage in CLL is associated with hypogammaglobulinemia, which triggers autoimmune problems — both AIHA and immune thrombocytopenic purpura. The treatment should include replacement therapy with intravenous immune globulin (IVIG).
Emmanuel Besa, MD
Thomas Jefferson University Hospital
Treat CLL with rituximab plus bendamustine.
Henrik Hjorth-Hansen, MD
Norwegian University of Science and Technology
I would check for the mutational status and, if it is the mutated form of CLL, I would offer her fludarabine, cyclophosphamide, and rituximab (FCR), as he could be cured of her disease. If she is unmutated, I would offer her ibrutinib as a single agent.
Eduardo Edmundo Reynoso, MD
I would suggest splenectomy after vaccinating the patient with pneumococcal, meningococcal, and Haemophilus influenzae vaccine, even though he may not be able to mount a good antibody response with CLL after tapering steroids.
Marion Sternbach, MD
- Re-treat with rituximab along with continued low-dose prednisone. A few of my patients with AIHA have responded to rituximab plus prednisone on two separate occasions, two years apart, with return of hemolysis when prednisone alone was continued. I have had good responses when I institute maintenance rituximab therapy: one dose per month initially, then add prednisone 20 mg/day for seven days each month. After three cycles with no recurrence of hemolysis, I administer every three months for one year. Assuming that it works, I may reduce the frequency, such as to every four months. This is all clinical/empirical evidence.
- Have you tried any other immune suppressive agents? I have had success when I substitute prednisone for cyclosporine. I also have had success when I add cyclophosphamide (oral or intravenous) to rituximab plus prednisone.
- If the above two methods are not suitable, ibrutinib is worth consideration. Ibrutinib has proven efficacy in CLL, but not particularly against AIHA. But in a carefully monitored patient, substituting prednisone with ibrutinib plus rituximab (weekly for 4 weeks, followed by monthly for 4 or 6 months) might be another alternative. The activity of a Bruton tyrosine kinase inhibitor is proven against B cells but it might also have some activity in T cells.
- Splenectomy: Since the emergence of efficacy of rituximab (rituximab-cyclophosphamide-dexamethasone, rituximab-prednisone, etc) in AIHA, the use of splenectomy has become markedly lower. Splenomegaly was noted at the time of first presentation of this patient but was not mentioned again. Is it still palpably enlarged? In any case I would consider this option, but it is not very high on my list. If done laparoscopically, it can be effective. I would also like the colleagues in the Blood Bank to recheck a Coombs test, in addition to warm IgG antibodies. Is there evidence of complement-based hemolysis? I assume hemolysis-related factors such as haptoglobin, reticulocyte count, LDH, etc. are being followed.
Kanti Rai, MD
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health
Lawrence Rice, MD
I would use first. If this is not effective, I would administer obinutuzumab with bendamustine.
Samo Zver, MD
University Hospital Center Ljubljana
I would use obinutuzumab to achieve deep response and control minimal residual disease in the bone marrow.
Vladimir I. Vorobyev, MD, PhD
National Research Center for Hematology
Robert Birdwell, M.D., FACP
St. Elizabeth Hospital
Since the patient has an AIHA that does not respond to corticosteroids, I would treat him with a CLL-specific immunochemotherapy regimen, such as:
- Fludarabine, cyclophosphamide, and rituximab in the case of mutated immunoglobulin variable region heavy chain [IGHV] and no comorbidities;
- bendamustine plus rituximab in the case of mutated IGHV in the presence of comorbidities;
- ibrutinib in the case of unmutated IGHV in the presence of comorbidities; or
- obinutuzumab/chlorambucil for frail patients or when creatinine clearance is < 60 mL/min or in the presence of ibrutinib contraindication.
Stamatis Karakatsanis, MD, MSc
University of Athens
I would be hard pressed to think he would receive additional benefit with only five months of response to the last CD20-directed therapy. At this point, I would be most concerned about the long-term consequences of chronic prednisone use, which is not working and is causing more harm than good. When we think of additional classical treatment for AIHA (that is not associated with a frank hematological malignancy per World Health Organization criteria), the risks of additional traditional immunosuppression also likely outweigh the benefits considering that this patient’s hemolysis may respond to direct CLL treatment. Preliminary data from the appear encouraging for ibrutinib in early-stage CLL in terms of progression-free survival and time to next treatment vs. placebo. Although complete response rates are low with single-agent ibrutinib (which may or may not be enough to suppress the clone causing his hemolysis), the risk of ibrutinib in this particular patient appears to be low (i.e., he is not on anticoagulation and does not have significant cardiac disease). Alternatively, one could try IVIG, especially if the patient has a low normal immunoglobulin level, although we do not classically think of IVIG as the best treatment for AIHA. I would share decision-making with the patient. I would not subject him to fixed-duration venetoclax/obinutuzumab at this time, but would consider it if ibrutinib and/or IVIG is not working.
William Johnson, DO
Thomas Jefferson University
Switch to ibrutinib as single agent. Most likely to result in continued control and adequate hemoglobin.
Evan Slater, MD
Ventura County Medical Center
I would consider adding ibrutinib 420 mg orally daily indefinitely. He has recurrent hemolysis and splenomegaly. If hemolysis is not controlled, I would add obinutuzumab.
William Caceres, MD
San Juan VA Medical Center
Rio Piedras, Puerto Rico
I would add cyclosporine to prednisone.
Michalis D. Michael, MD, PhD
If his hemoglobin level is >100 g/L ad there are no other major comorbidities, I would wait and watch. Otherwise, ibrutinib trial for three to six months at 420 mg/day or, if ineffective, try venetoclax or idelalisib. Perform splenectomy only as a last resort.
Michael Pidcock, MBBS
As this patient has already been treated with prednisone and rituximab, splenectomy would be a reasonable option for achieving long-term remission. This procedure can be safely done laparoscopically. The patient should be vaccinated against encapsulated organisms, preferably prior to the procedure. Given chronic hemolysis, consideration should be given to folic acid replacement.
Hamza Hashmi, MD
Moffitt Cancer Center
I would give him ibrutinib monotherapy, which works amazingly well for AIHA + CLL. There is no need to add rituximab because it is not severe hemolysis. He is 65 years old, so I think it is okay to give prolonged therapy. In a younger patient, I would prefer to withdraw from lifelong therapy. In this case, you can’t achieve stable response of AIHA until you control the CLL.
Eugene Nikitin, MD, PhD
S.P. Botkin Hospital