Discussion
We report herein the first success to our knowledge of eculizumab for
the treatment of wAIHA occurring in a patient with CMML.
Even if accurate data are lacking concerning the prevalence of
inflammatory or autoimmune diseases in CMML patients, monocentric
studies suggest that AID may occur in about 20% of cases (1,2). The
outcome of patients with CMML-associated AID remains unclear, but in
most cases, they exhibit rather favorable prognostic features of the
underlying myeloid disorder. In a retrospective study of 377 CMML
patients, those with AID were more likely to have a lower risk
prognostication based on the Mayo Clinic prognostic model (1). Results
were similar in a French retrospective study (3). In a third cohort,
cytogenetic abnormalities seemed less frequent in CMML patients with AID
(2). Finally, in a small cohort focusing on CMML-associated ITP, all
cases of immune thrombocytopenia occurred in patients with
low-risk CMML, and none of them experienced CMML progression or
transformation into acute myeloid leukemia during follow-up (4).
Considering our patient, CMML has remained stable with a follow-up of 17
years.
Among AIC, the development of ITP seems much more frequent than AIHA.
Thus, the only available data reporting efficacy of treatments in
CMML-associated autoimmune cytopenias concern patients with ITP. In
nearly all reported cases of CMML-associated AID, first-line treatment
consisted of corticosteroids, and most relapsed patients received
immunosuppressive therapies. Focusing on ITP, successful treatments with
corticosteroids, rituximab, splenectomy or thrombopoietin agonists have
been reported, and some authors consider that CMML‐associated ITP should
be treated according to current guidelines for primary ITP (4). The same
rationale could apply to CMML-associated AIHA and in our patient;
splenectomy led to a durable control of AIHA for about 10 years.
In AIC associated with lymphoproliferative disorders such as chronic
lymphocytic leukemia, most experts believe that an optimal control of
the malignant clone would represent the best option to control
autoimmune manifestations. The same hypothesis could be raised in
CMML-associated AID. The rationale for the use of 5-azacitidine in this
setting, even in the absence of CMML progression, is based on its
ability to remove or at least to lower the tumor clone. Some studies
have reported efficacy of 5-azacitidine in autoimmune manifestations
associated with myelodysplastic syndromes or CMML but none of them was
AIHA. A prospective phase II trial, supported by French Group of
Myelodysplasia (NCT02985190), is currently evaluating the efficacy and
safety of 5-azacitidine in refractory autoimmune and inflammatory
diseases associated with myelodysplastic syndromes, and may provide
answers for clinicians. However, azacitidine cannot be considered as a
salvage treatment in case of life-threatening AIC because responses are
usually delayed (6,7). Moreover, its initial myelotoxicity may worsen
the cytopenias.
The use of eculizumab is not approved for AIHA. A prospective phase II
trial reported its efficacy in patients with CAD (8). These results can
be explained by the central role of terminal complement activation in
cold AIHA. The use of eculizumab has already been reported in a case of
wAIHA associated with Waldenström macroglobulinemia (9). In this case,
wAIHA was also refractory to steroids, rituximab and plasmapheresis. As
in our patient, DAT was positive for both IgG and C3d. After four weekly
doses of eculizumab hemoglobin was stabilized around 90 g/L and
treatment was stopped. The patient remained in partial remission for
four months before he died from refractory anemia relapse. The
complement system plays an important role in the physiopathology of
AIHA. Some patients, including our case, suffer from wAIHA with both IgG
and C3d positive DAT. In these specific forms, autoantibodies,
especially IgM, can activate the complement system in vivo ,
leading to the destruction of red blood cells. These IgM, which react at
37°C, contribute to hemolysis by activating the classical pathway of the
complement system. Meulenbroek et al. showed that all patients
with C3 on their red blood cells have an IgM component that could
activate complement even if no such antibody could be detected with
routine techniques (10). In wAIHA with positive DAT for C3d,
complement-mediated red blood cell destruction contributes to the
severity of acute hemolysis, exacerbations of chronic AIHA and poor
performance of red blood cell transfusions. For these patients, use of
eculizumab could prevent red blood cell transfusions, which can
exacerbate hemolysis, or could restore the transfusion efficiency, while
waiting for the effect of the other treatments. In addition to its cost,
the suspensive effect and the risk of severe bacterial infections such
as meningococcal infection could represent the main limitation of
eculizumab (11). In this specific population, it is of major interest to
consider the safety profile of eculizumab since previous exposure to
corticosteroids or other immunosuppressive agents might increase even
more the risk of severe infections. We did not observe any infectious
complication during our patient’s treatment with eculizumab. In the
prospective study on CAD, Röth et al , reported one case of
treatment-related pneumonia among 13 patients treated with eculizumab
(8). No meningococcal infection was observed.
In our case, a delayed effect of rituximab cannot be formally ruled out
but the efficacy of this treatment is usually not observed beyond three
months (12). The concomitant correction of thrombocytopenia is a further
argument for rituximab late effect because of its proven efficacy in
both primary and secondary ITP (13). Moreover, complement system has not
been involved in autoimmune thrombocytopenia until now. Whether
eculizumab should have been pursued such a long time in our patient is
questionable. In the phase 2 study on CAD, eculizumab was given for 26
weeks (8). As our patient did not experience any infectious complication
and because of the severity of AHAI presentation, eculizumab was
maintained up to 56 weeks, but it may have been stopped earlier. One
year after the end of treatment, no relapse has occurred so far. In case
of AIHA relapse, a new course of rituximab or 5-azacitidine could be
considered but since these agents have an expected delayed efficacy,
eculizumab should be rechallenged if needed.