Reader Responses: Is hypogammaglobulinemia alone an indication for treatment for CLL?

Here’s how readers responded to a You Make the Call question about whether hypogammaglobulinemia alone is an indication for treatment of CLL.

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 strongly favor treating this patient for CLL since he had pneumocystis pneumonia infection and has a functional defect in humoral immunity. His history of prior infection portends high risk for future infections. Although he does not have cytopenias, the defect in B cell production of IgG is due to the underlying lymphoproliferative disorder and requires treatment.

Shyam A. Patel, MD, PhD
Worcester, MA

It depends on the patient’s immune status. If the patient is clinically symptomatic with recurrent infections that are affecting daily life, then I do think it’s appropriate to treat.

Deborah Vaz, MBBS
Pretoria, South Africa

No. Treatment of CLL usually does not help to ameliorate the hypogammaglobulinemia, even if a complete remission is achieved. If CLL with hypogammaglobulinemia is complicated by repeated infections, Ig substitution may lead to lesser infections. I do not know whether Ig substitution confers protection against pneumocystis in particular. I suspect it will not help because immunity to that particular pathogen is based on cellular defense mechanisms.

Christian Rudolph, MD
Eberswalde, Germany

The fact that the patient had a serious opportunistic infection indicates he is compromised from his CLL and needs treatment.

Divis Khaira, MD
Oceanside, CA

Yes, should proceed to treatment.

William Robinson, MD, PhD
Aurora, CO

I would continue the immune globulin and would not start treatment for the leukemia.

Joseph R. Holahan, MD
San Antonio, TX

I would infuse IVIG to keep the IgG level at 600 mg/dL or higher, treat infections, and watch. If the patient has repeated infections despite keeping IgG at a higher level, I would treat the CLL.

Phillip Periman, MD
Amarillo, TX

I would not typically treat CLL for hypogammaglobulinemia. I would continue on IVIG with the expectation that the Ig levels will improve with monthly infusions.

Myron Bednar, MD
Flemington, NJ

No, it is not an indication for treatment.

Márk Plander, MD, PhD
Szombathely, Hungary

Guidelines for instituting immunoglobulin replacement therapy in CLL include: IgG <4g/L (without paraprotein) with recurrent infections on prophylactic antibiotics for longer than 6 months; preferably with low specific antibodies to antigens (tetanus, Haemophilus influenzae B, pneumococcus) even after vaccination.

Sujoy Khan, FRCP, FRCPath
Cottingham, U.K.

The patient’s underlying CLL and low gamma globulins already predisposed him to pneumocystis pneumonia. Despite no cytopenia, the risk of recurrent infections is possible. He is a candidate for treatment of his underlying disease process.

Theresa Laurent, MD
Bridgetown, Barbados

I think that, in absence of illness, treatment may not be necessary. If the patient is undergoing aggressive therapy or has risk factors, I would recommend IgG replacement. I have seen only one patient who required it, due to refractory pneumonia.

David Ross, MD
Cherry Hill, NJ

No, hypogammaglobulinemia alone, even in the context of infectious episodes, is not an indication for CLL specific treatment. I would give the patient monthly Ig as prophylaxis for infectious episodes.

José Ignacio Trucco, MD
Buenos Aires, Argentina

I doubt it would be an indication for treatment unless the patient’s symptoms are clearly attributable to hypogammaglobulinemia (and not asymptomatic hypogammaglobulinemia alone). Even then, if IVIG prevents recurrent infections, CLL-directed treatments could be delayed.

Shyam Balepur, MD
Lancaster, PA

I would not treat on the basis of hypogammaglobulinemia alone but would provide regular supplemental IVIG and provide closer surveillance for a treatment trigger.

John Hounsell, FRACP, FRCPA, MBBS
Warrnambool, Australia

No, it is not an indication for treatment since the hypogammaglobulinemia does not respond to treatment.

Robert A. Moss, MD
Fountain Valley, CA

There is no indication for IVIG in this patient, regardless of his IgG level.

Elias J. Anaissie, MD
Covington, KY


Brice Weinberg, MD
Durham, NC

Does this patient have idiopathic CD4 lymphopenia? It is odd to see pneumocystis pneumonia infection in indolent CLL, even in the face of marked IgG deficiency. Nonetheless, with a single bout of life-threatening infection in the setting of severe hypogammaglobulinemia, I would administer monthly IVIG. I would repeat the HIV assay in the near term.

 Peter V. Pickens, MD
Wayne, PA

This is a very interesting dilemma that we have also faced in treating patients with Waldenström macroglobulinemia (WM). CLL and WM share many features, including a potential common ancestor in the memory B cell. Both diseases also respond very similarly to therapeutics, including Bruton tyrosine kinase (BTK) inhibitors. Like CLL, most patients with WM present with hypogammaglobulinemia. We therefore looked at the impact of treatment on hypogammaglobulinemia (Hunter et al., Haematologica 2006). Our study found that patients treated with chemoimmunotherapy had lower levels of IgG and/or immunoglobulin A (IgA) as a consequence of therapy and did not recover during the long study follow-up. Moreover, even patients who had obtained a complete remission did not show rebound of their IgG and IgA antibodies during follow-up. Many of the patients developed recurring sinobronchial infections, necessitating antibiotics and/or IVIG treatment. In the modern era, we found that BTK inhibitors did not affect IgG and/or IGA levels. A new paradigm may exist, but our experience would suggest that hypogammaglobulinemia alone should not be an indication for therapy.

Steve Treon, MD, PhD
Boston, MA


Margaret E. Rick, MD
Bethesda, MD

Yes. I would advise continuing immunoglobulin and repeating testing either by fluorescence in situ hybridization (FISH) or flow cytometry to make sure that this patient does not have other adverse features.

Nyaba Emmanuel Yamusah, MD
Paterson, NJ

Immune dysregulation is commonly seen in patients with CLL. However, as with autoimmune complications, I would first treat immune dysregulation with specific treatments. In this case, in pneumocystis pneumonia (and HSV/VZV) prophylaxis, IVIG therapy may be appropriate and sufficient. In addition, pneumocystis pneumonia in CLL is an indicator of both humoral and cellular immunity compromise. It would have been interesting to know the CD4 count in the case referred here.

Patients that receive the BTK inhibitor ibrutinib have been studied, and immunoglobulin levels may actually further decrease while on therapy, but it remains to be seen if this decline is clonal or polyclonal. There is a higher risk of “infections and infestations” in the first 6 months of BTK therapy, which plateaus in the following 4.5 years (now with more than 5 years of follow-up for newly diagnosed and relapsed/refractory populations. I have personally treated two of these patients recently, and with proper pneumocystis pneumonia prophylaxis, the problem never recurred.

Julio Hajdenberg, MD
Orlando, FL


Patrick Duffy, FRCPC, MD
Regina, Saskatchewan, Canada


Jacinta Meharchand, FRCPC
Toronto, Ontario, Canada


Pablo Rios Rull, MD, PhD
Santa Cruz de Tenerife, Spain

Hypogammaglobulinemia alone is not an indication to start monthly infusions. It is indicated in patients with IgG levels below 500 mg/dL and with frequent infections. In addition to IVIG, I would add trimethoprim/sulfamethoxazole (one tablet three times per week) and measure CD4 counts.

William Caceres, MD
Rio Piedras, Puerto Rico

I would not treat this patient with IVIG unless a serious bacterial infection is documented. IVIG may not be effective in pneumocystis pneumonia.

Michael Pidcock, MBBS, FRACP, FRCPA
Canberra, Australia