Q:

Do you have any general thought on treating recalcitrant sinusitis with IVIG in a elderly gentleman with hypogammaglobulinema (IgG 300) being treated for Mantle Cell Lyphoma with Rituximab?

A:

Thank you for your recent inquiry.

In brief, I think that your patient is certainly a candidate for immunoglobulin replacement therapy. However, I would probably first proceed with assessing his immune response to pneumococcal immunization to document that he is functionally deficient in the production of immunoglobulins.

The rationale for immunoglobulin replacement therapy in patients taking Rituximab has been a topic of our website, in a different clinical scenario, previously. You might be interested in that question and our response as well because it presents some literature which might be helpful to you. I have thus copied this previously submitted question and our response below.

In summary, however, as you can see from the bolded font in our previous response, the weight of evidence is supportive of the use of immunoglobulin replacement therapy in such patients.

Thank you again for your inquiry and we hope this response is helpful to you.

Q: This is a 55 year old man with a history of symptomatic Waldenstrom's Macroglobulinemia who was treated with maintenance Rituximab from 2006-2008/9, now with no evidence of disease. However he has developed a known complication of Rituximab therapy: hypogammaglobulinemia. IgG=223, IgA=6, IgM=143 in 7/11. Levels were similar in 1/11 (but nl at diagnosis). He had Pneumovax in 1/11 with undetectable response to 21/23 serotypes measured 2 months later.

However, he has no history of infections at all. He has no other medical conditions. No known bronchiectasis. CBC and SPEP are now normal. IgG to Tetanus is nl. I requested he be vaccinated with Prevnar.

My questions are:
1) Assuming an equally poor response to Prevnar, would you place this patient on immune globulin replacement without a history of infection? Should I even wait for the response to Prevnar?

2) Have you seen this due to Rituxan before, and how long does the hypogamm last?

3) Is he at risk for bronchiectasis and does that justify IVIG?

Answer: Thank you for your recent inquiry.
Unfortunately I cannot personally give you an answer to your questions. Although there is evidence that immunoglobulin replacement therapy can be helpful in regards to prolonging life and preventing infections in patients with multiple myeloma (see abstract copied below), and I have used replacement therapy in this disease, I have no personal experience in treating patients with Waldenström’s with immunoglobulin replacement. Unfortunately, the literature search I performed gave very little helpful information.
I did find one article, the abstract of which is copied for you below, which implies that the level of immunoglobulins G and A do not correlate with the presence of infection. Evidently there has been a trial of immunoglobulin replacement, but the article was in German (title of article copied below), and I did not have access to the article.
Because I cannot give you a satisfactory answer, I am going to ask for help from Dr. Steven Treon, who is Director of the Bing Center for Waldenström’s Research, Associate Professor in Medicine, at Harvard Medical School.
As soon as I receive Dr. Treon’s response, I will forward it to you. Thank you again for your inquiry.
Mediterr J Hematol Infect Dis. 2010 Apr 20;2(1):e2010005.
Effect of immunoglobulin therapy on the rate of infections in multiple myeloma patients undergoing autologous stem cell transplantation or treated with immunomodulatory agents.
Khalafallah A, Maiwald M, Cox A, Burns D, Bates G, Hannan T, Seaton D, Fernandopulle B, Meagher D, Brain T.
Source
Launceston General Hospital, Launceston, Tasmania
Abstract
Multiple myeloma (MM) is associated with a significant risk of infection due to immune dysfunction. Infections are a major cause of morbidity and mortality in MM patients. There are few data available regarding the prevalence of infection in MM patients, especially in conjunction with newer generations of immunomodulatory drugs (thalidomide, bortezomib, lenalidomide) or post autologous stem cell transplantation (ASCT). Intravenous immunoglobulin (IVIG) has been used successfully to reduce infection rates in the stable phase of MM, with limited data in other stages.We retrospectively analyzed 47 patients with MM from March 2006 to June 2009 at our institution. All patients received thalidomide and steroid therapy for at least 6 months. Nine patients received bortezomib and 11 lenalidomide subsequent to thalidomide, because of disease progression, and 22 patients underwent ASCT. The median age was 64 years (range 37-86), with a female-to-male ratio of 18:29. The median residual-serum IgG-level at time of infection was 3.2 g/L, IgA 0.3 g/L and IgM 0.2 g/L. Most patients suffered from recurrent moderate to severe bacterial infections, including the ASCT group. Fifteen patients suffered from different degrees of viral infections. All patients except 3 received IVIG therapy with a significant decline of the rate of infection thereafter (p<001). Our analysis shows that patients with MM treated with the new immunomodulatory drugs in conjunction with steroids are at significant increased risk of infection. Employing IVIG therapy appears to be an effective strategy to prevent infection in this cohort of patients. Further studies to confirm these findings are warranted.
Published online 10 November 2009
Haematologica, Vol 95, Issue 3, 470-475 doi:10.3324/haematol.2009.010348
Background: Hypogammaglobulinemia is common in Waldenström’s macroglobulinemia. The etiology of this finding remains unclear, but it has been speculated to be based on tumor-induced suppression of the ‘uninvolved’ immunoglobulin production.
Design and Methods: We evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 untreated patients with Waldenström’s macroglobulinemia and investigated the associated clinicopathological findings and impact of therapy. We also sequenced eight genes (AICDA, BTK, CD40, CD154, NEMO, TACI, SH2D1A, UNG) implicated in immunoglobulin deficiency in 19 Waldenström’s macroglobulinemia patients with IgA and/or IgG hypogammaglobulinemia.
Results: At baseline 63.3%, 58.0% and 49.3% of the 207 patients had abnormally low serum levels of IgA, IgG, or both. No association between IgA and IgG hypogammaglobulinemia and disease burden, serum IgM levels, b2-microglobulin, International Prognostic Scoring System score, or incidence of recurrent infections was observed, although the presence of adenopathy and/or splenomegaly was associated with a lower incidence of hypogammaglobulinemia. Lower IgA and IgG levels were associated with disease progression in patients managed with a ‘watch and wait’ strategy. IgA and/or IgG levels remained abnormally low despite response to treatment, including complete remissions. A missense mutation in the highly conserved catalytic site of UNG was observed in a patient with hypogammaglobulinemia, warranting further study of this pathway in Waldenström's macroglobulinemia.
Conclusions: IgA and IgG hypogammaglobulinemia is common in Waldenström’s macroglobulinemia andpersists despite therapeutic intervention and response. IgA and IgG hypogammaglobulinemiadoes not predict the risk of recurrent infections in patients with Waldenström’s macroglobulinemia, although lower levels of serum IgA and IgG are associated with disease progression in Waldenström's macroglobulinemia patients being managed with a ‘watch and wait’ strategy.
Beitr Infusionther Klin Ernahr. 1983;11:52-8.
[Intravenous immunoglobulin substitution in patients with multiple myeloma, Waldenstrom's syndrome and chronic lymphatic leukemia with secondary antibody deficiency syndrome].
[Article in German]
Schedel I.
Sincerely,
Phil Lieberman, M.D.

Additional information:
Thank you Dr. Lieberman for your response. But I would like to clarify something. This patient's hypogammaglobulinemia is not due to Waldenström’s, but rather the treatment of his Waldenström’s, Rituximab. He did not have hypogammaglobulinemia during the course of illness. Only now after Rituximab does he have hypogammaglobulinemia, so I'm not sure the 'lack of associated infection' found in Waldenström’s hypogamm applies in this patient.
Thank you again.
Addendum Response from Dr. Lieberman:
Thank you for clarifying the situation regarding your thoughts as to the cause of the hypogammaglobulinemia. As you know, hypogammaglobulinemia occurs during Waldenström’s. It has certainly, as you noted, been reported with the use of rituximab.
However, it is my impression that the majority of these reports are in cases who have been treated with rituximab plus another chemotherapeutic agent. I have copied abstracts for you below which illustrate the phenomena occurring with such combination therapy. It may be, however, that you are certainly correct, and rituximab alone could be responsible.
There is certain precedent for using immunoglobulin replacement therapy in patients who have hypogammaglobulinemia related to combination therapy with rituximab and another chemotherapeutic agent. One abstract copied below illustrates one such case.
However, since most of these cases, at least all that I have seen in the literature, were due to rituximab plus another agent, and you did not describe the administration of another agent, and since Waldenström’s itself can produce hypogammaglobulinemia, I could not be sure that rituximab played a role in the production of your patient’s hypogammaglobulinemia. This is the case even though they did not have it prior to the rituximab since the natural history of Waldenström’s indicates that the hypogammaglobulinemia can occur later in the course of the disease, and not be present in its early stage.
If of course this patient did receive another chemotherapeutic agent, then that would of course make rituximab far more likely as the cause.
Regardless, I think we are still left with the same conundrum; that is, whether or not to administer immunoglobulin to this patient. Having no experience in this regard, before responding to your question, I felt it best to have access to someone with far more experience in this area, and I still believe we should await the response from Dr. Treon before proceeding.
Nonetheless, since we are discussing the issue further, I will go ahead and deal briefly with the other specific questions you asked.
Unfortunately, I do not think anyone can predict the risk of bronchiectasis in this patient. And, as you can see from the abstracts we sent, Rituxan, in combination with another chemotherapeutic agent, can produce a very profound and very prolonged hypogammaglobulinemia. So, it would not be unexpected that this, if due to the rituximab, could persist for years.
I do not think that the response to Prevnar would make much difference in this case. It would simply add a little more evidence to justify the use of Prevnar, but I would not be surprised, as you have noted, that this response would be very poor. Nonetheless, since he is not having any problems so far, I think you can at least await the Prevnar response, and hopefully we will have some word from our consultant in the meantime.

If we do not hear back from our consultant, I guess, taking all of the facts into consideration, and since immunoglobulin replacement therapy has been utilized in rituximab-induced (plus chemotherapeutic agent) hypogammaglobulinemia, the weight of evidence would support its use.

Finally, once again, I will forward you the response from Dr. Steven Treon as soon as we hear from him.
Thank you again.
Sincerely,
Phil Lieberman, M.D.
Cancer Invest. 2008 May;26(4):431-3.
Profound hypogammaglobulinemia 7 years after treatment for indolent lymphoma.
Walker AR, Kleiner A, Rich L, Conners C, Fisher RI, Anolik J, Friedberg JW.
Source
University of Rochester, Hematology/Oncology, Rochester, New York 14642, USA. alison
Abstract
We report a case of a previously healthy 31 year old woman diagnosed with Stage IIIA follicular lymphoma treated with fludarabine in combination with cyclophosphamide and rituximab who presented seven years after the completion of therapy with CD4 count depression, panhypogammaglobulinema and a history of recurrent sinus infections. We performed comprehensive immunophenotypic analysis and found her to have only 1.2% switched (normal 21 +/- 8%) and 4.7% non-switched (11 +/- 4%) memory B cells with 92% of B cells belonging to the naïve compartment. We have previously evaluated reconstitution of the B cell compartment during the 6 to 12 month recovery period after treatment with rituximab and found a similar immunophenotypic pattern. In our patient, this defect was observed seven years after the administration of rituximab in combination with an alkylating agent and purine analog. The patient was started on monthly intravenous immunoglobulin treatments with complete resolution of her symptoms.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011 Jun;19(3):676-679.
[Change of Serum Immunoglobulin Level in Patients with Diffuse Large B Cell Lymphoma after Rituximab Combined with Chemotherapy.]
[Article in Chinese]
Wang QS, Zhao Y, Wang SH, Li HH, Huang WR, Gao CJ, Yu L.
Source
Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
Abstract
This study was purposed to investigate the changes of serum immunglobulin (Ig) level during treatment of diffuse large B cell lymphoma by using rituximab (RTX) combined with CHOP. Total of 122 newly diagnosed patients with CD20(+) diffuse large B cell lymphoma from January 2004 to December 2009 were analyzed retrospectively. According to different treatment regimens, 122 patients were divided into 2 group: group treated with CHOP (n = 24) and group treated with R-CHOP (n = 98, out of which 16 patients with abnormal Ig levels before treatment). Ig levels of patients in 2 groups at different stages were recorded and analyzed after abandoning those patients with abnormal Ig levels before treatment. The results showed that after 6 cycles of treatment, among the total 82 patients with normal levels of serum immunoglubulin, the decreased levels of IgG, IgA and IgM by 20% of baseline value were found in 85.4% (70/82), 85.4% (70/82) and 87.8% (72/82) patients respectively, while levels of IgG, IgA and IgM < low limit of normal value were observed in 47.6% (39/82), 48.8% (40/82) and 52.4% (43/82) patients respectively. No obvious changes of IgG, IgA and IgM levels were found in 24 patients of CHOP group before and after treatment.It is concluded that hypogammaglobulinemia is a common complication in chemotherapy using RTX combined with CHOP, the decreased level of Ig is recovered to normal level about 1 year after stop of treatment, the decrease of Ig in some cases can last even for over 2 years.
Int J Hematol. 2010 Apr;91(3):501-8. Epub 2010 Mar 10.
Severe hypogammaglobulinemia persisting for 6 years after treatment with rituximab combined chemotherapy due to arrest of B lymphocyte differentiation together with alteration of T lymphocyte homeostasis.
Irie E, Shirota Y, Suzuki C, Tajima Y, Ishizawa K, Kameoka J, Harigae H, Ishii T.
Source
Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
Abstract
We report a case of prolonged severe hypogammaglobulinemia after rituximab combined chemotherapy for follicular lymphoma. Although the patient's globulin level was within the normal limits before treatment, the level of IgG dropped below 100 mg/dL, and both IgA and IgM became undetectable after treatment, and the levels have shown no changes for 6 years despite recovery of peripheral B cell counts. Phenotypic analysis of B cells revealed a reduction of class-switched CD27+IgM-IgD- memory B cells below 0.5% and overexpression of CD95. On the other hand, we observed the predominance of memory T cell subsets in both of CD4+ and CD8+ T cells as the result of reduction of naïve T cells. These increased memory T cells overexpressed activation markers such as CD69, CD95, and HLA-DR. Furthermore, the patient's B cells failed to differentiate into memory B or plasma cells in the presence of IL-6, IL-10, IL-15, and BAFF in vitro in comparison with those from healthy controls and showed significant impairment of IgG production. These findings suggest that rituximab combined chemotherapy may induce persistent differentiation arrest and apoptosis of B cell lineage with alteration of T lymphocyte homeostasis resulting in pan-hypogammaglobulinemia.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology