A “Rose” by Any Name..

TerryHamblinA significant sub-group of CLL patients are diagnosed with something called SLL (small lymphocytic lymphoma). If like many of us you feel that CLL does not get much respect when compared to more frequent blood cancers such as non-Hodgkin’s lymphoma, just think what SLL folks go through.  They get either of two almost flippant viewpoints from many experts:

  • (1) CLL and SLL are the same disease, the WHO says they are, so stop bothering us.
  • (2) SLL is a lymphoma, the very name says it is a lymphoma, so treat it like a lymphoma and get done with it.

Neither of these slam dunk choices is quite satisfactory to patients diagnosed with the SLL variant of CLL. No wonder SLL patients are confused and frustrated.  Well guys, here is your chance to learn more about it. And if you log in you can participate in the discussion that follows, perhaps ask questions of the expert.

Dr. Terry Hamblin needs no introduction in any CLL patient community. I and my husband PC had the pleasure of meeting him in Bournmouth, UK.  There is a story behind that meeting that I would like to share with you.

After several cycles of Rituxan therapy PC became hypersensitive to the mouse component of Rituxan and was forbidden to use it ever again. Ofatumumab (“Arzerra”, “Humax-CD20″) was still in clinical trials and not FDA approved.  But the company agreed to let PC have “compassionate use” access to the drug.  We were delighted! But our happiness was short lived when each and every USA CLL expert that we contacted declined with regret to administer the drug.  It seems there was too much paperwork and they just could not find a way of finessing the redtape.  I wrote to Terry, pleading for his help.  Within 24 hours he wrote back and said if we can come to the UK he is both willing and able to administer the drug.  Terry and I spent big chunks of time discussing CLL and all things hematological while PC was getting his four infusions.  I learnt more hematology during those sessions with Terry than at any other time.  The ofatumumab infusions bought PC another year and half of precious life. I will never forget the debt I owe this brilliant and compassionate physician / researcher.

Without more preamble, here is Terry’s take on SLL.  I took no editorial liberties with his text.  But I could not resist adding a bit of highlighting and bolding here and there.  I also added bits and pieces where I thought it might be useful information for our members.  But my editorial comments are color coded in blue, so that you can tell where I have meddled.


SLL as opposed to CLL

Dr. Terry Hamblin

The WHO refers to them as a single disease but patients worry whether they really are. Small lymphocytic lymphoma (SLL) has the same diagnostic markers as chronic lymphocytic leukemia (CLL) – CD5+, CD19+, CD23+, weak surface Ig, weak CD79b, and FMC7 negative – but it is a lymphoma and not a leukemia. Is SLL just CLL situated somewhere else or does it really need a different approach?

Obviously there is some difference. By definition, SLL does not appear in the blood. Presumably the cells have something different about them – they must have some increased tendency to go to lymph nodes than blood or bone marrow.

When CLL appears in the lymph nodes, the histological pattern is that of SLL, and when SLL eventually appears in the blood, as it does in 25% to 50% of cases, the picture is that of CLL. But SLL tends to end up in the hands of oncologists and CLL in the hands of hematologists.

The IWCLL definition of SLL requires enlarged lymph nodes with the same tissue morphology and immunophenotype as CLL with no cytopenias due to bone marrow infiltration and fewer than 5 x 109/L peripheral blood B cells. Some would also suggest that there should be less than 30% lymphocytic infiltration of the bone marrow, though this is disputed. Most CLL specialists have only seen rather few cases of SLL, and for this reason only small series of cases (around 30 cases) have been reported. It seems that SLL is only about one tenth as common as CLL.

Researchers have sought for differences between CLL cells and SLL cells. It has been reported that they express different chemokine receptors. Chemokines are chemicals that induce cells to migrate to different tissues. CLL cells strongly express CCR1, CCR3, CCR6 and CCR7; SLL cells only express CCR6 [1, 2]. The lymphocytotoxin- gene, which has an important function in the regulation of the immune response, is expressed at a much lower level in SLL cells compared to CLL cells [3]. At present these differences are of research interest only and have no practical implications for either diagnosis or treatment of SLL.

The usual prognostic markers – FISH, IgHV gene mutations, CD38 and ZAP-70 have the same implications for CLL and SLL, but a recent publication suggests that trisomy 12 and the use of the poor prognostic IGHV gene V3-21 are commoner in SLL than CLL [4].

Therapy Options

It is when it comes to treatment that differences occur. As it is a lymphoma, the Ann Arbor system of staging is used for SLL.

  • Ann Arbor staging is the staging system for lymphomas. It was initially developed for Hodgkin’s disease, but is used for non-Hodgkin’s disease as well. Stages are determined by location of the tumor:
  • Stage I : the cancer is located in a single region, usually one lymph node and the surrounding area. Stage I often will not have outward symptoms.
  • Stage II : the cancer is located in two separate regions, two different lymph nodes or organs, and both affected areas are confined to one side of the diaphragm – that is, both are above the diaphragm, or both are below the diaphragm.
  • Stage III: the cancer has spread to both sides of the diaphragm.
  • Stage IV: indicates diffuse or disseminated involvement of more than just lymph nodes, including any involvement of the liver, bone marrow, or lungs.

While this is entirely inappropriate for CLL, in SLL it provides for a potentially curative treatment. In stage 1 or stage 2 disease – where the lymphoma is localized to single group of lymph nodes or at least lymph nodes on one side of the diaphragm, the disease is potentially curable by involved field or extended field radiotherapy with 80% freedom from relapse in stage 1 and 62% freedom from relapse in stage 2 [5].

J Clin Oncol. 1989 May;7(5):598-606.

Small lymphocytic lymphoma.

Morrison WH, Hoppe RT, Weiss LM, Picozzi VJ Jr, Horning SJ.

Department of Radiation Oncology, Stanford University, CA.

The clinical course of 54 patientswith small lymphocytic lymphoma (SL) was reviewed. The majority of patients had disseminated lymphoma at the time of diagnosis; 14 patients (26%) presented with Ann Arbor stage I and II disease. Five- and 10-year survival for all patients was 76% and 49%. The only clinicopathologic features identified that predicted a shortened survival were the presence or absence of systemic (B) symptoms (15% v 63% at 10 years, P = .01) and a diffuse rather than pseudofollicular nodal architecture (47% v 87% at 10 years, P = .04). Initial bone marrow involvement was not an adverse prognostic factor for patients who presented with stage III and IV disease. Ten patients developed a marked lymphocytosis consistent with progression to a leukemic phase (chronic lymphocytic leukemia [CLL]). These ten patients had a median initial lymphocyte count of 2,790, compared with 1,580 for those patients who did not progress to CLL (P = .0001). Developing CLL did not adversely affect survival (P = .48). Thirty-seven patients were treated with various combinations of radiation and chemotherapy; 17 patients received no initial therapy. Ten-year freedom from relapse (FFR) for stage I and II patients treated with irradiation was 80% and 62%; FFR for stage III and IV treated patients was 11%. Despite the marked differences in FFR, no statistically significant difference in survival could be demonstrated between the various stages. Selected patients with advanced SL received no initial therapy; these patients had a 10-year survival that was not statistically different from the immediately treated stage III and IV patients. Patients with stage I and II SL should be treated with irradiation; prolonged FFR and possibly cure of the disease can be achieved in these patients.

PMID: 2651577


J Clin Oncol. 1996 Apr;14(4):1282-90.

Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University.
Mac Manus MP, Hoppe RT.

Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA, USA.

PURPOSE: To evaluate retrospectively the results of radiotherapy for 177 patients with stage I (n = 73 [41%]) and II (n = 104 [59%]) follicular small cleaved-cell and follicular mixed small cleaved-cell and large-cell non-Hodgkin’s lymphoma (NHL) treated in the Department of Radiation Oncology, Stanford University between 1961 and 1994. PATIENTS AND METHODS: Histology was follicular small cleaved-cell in 101 (57%) cases and follicular mixed small cleaved-cell and large-cell in 76 (43%). Forty-five patients (25%) had staging laparotomy; 34 (19%) had extranodal involvement. All patients had received radiotherapy, either to one side of the diaphragm (involved or extended field) or to both sides (total lymphoid irradiation [TLI] or subtotal lymphoid irradiation [STLI]. Radiotherapy doses ranged from 35 to 50 Gy. RESULTS: The median follow-up duration was 7.7 years. The longest follow-up duration was 31 years. Actuarial survival rates at 5, 10, 15, and 20 years were 82%, 64%, 44%, and 35%, respectively. The median survival time was 13.8 years. At 5, 10, 15, and 20 years, 55%, 44%, 40%, and 37% of patients, respectively, were relapse-free. Only five of 47 patients who reached 10 years without relapse subsequently developed recurrence. Survival and freedom from relapse (FFR) were significantly worse for older patients. Relapse rates were lower following treatment on both sides of the diaphragm or staging laparotomy. Univariate analysis showed that youth and staging laparotomy were associated with significantly better survival and that FFR was better following treatment on both sides of the diaphragm or laparotomy. CONCLUSION: Radiotherapy remains the treatment of choice for early-stage low-grade follicular lymphomas. Patients who have remained free of disease for 10 years are unlikely to relapse.

PMID: 8648385

For advanced stage disease treatment is the same as for CLL, except that local symptoms are more commonly controlled by radiotherapy (though hematologists often forget that this is an option for CLL also). The real problem is when to begin treatment. So many indications to begin treatment in CLL are related to the blood count that when to start with SLL may be confusing. Obviously the appearance of B symptoms or of cytopenias is an indication for both, but it is not clear what degree of enlarged lymph nodes or spleen should trigger treatment. Generally people talk about symptomatic enlargement as being the indication to start. My own feeling, now that FCR has been shown to be a better treatment than any other, is that very large lymph nodes with a largest diameter of 10 cm should be an indication to begin, but the only practical way of establishing this for abdominal glands is by CT scan. So perhaps here is a reason for using CT scans. Even so it should be possible to select those patients who need a CT by judicious use of ultrasound.


1. Wong S, Fulcher D. Chemokine receptor expression in B-cell lymphoproliferative disorders. Leuk Lymphoma 2004; 45:2491–2496.

2. Trentin L, Cabrelle A, Facco M, et al. Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas. Blood 2004; 104: 502–508.

3. Nagy B, Ferrer A, Larramendy M, et al. Lymphotoxin beta expression is high in chronic lymphocytic leukemia but low in small lymphocytic lymphoma: a quantitative real-time reverse transcriptase polymerase chain reaction analysis. Haematologica 2003; 88:654–658.

4. Daudignon A, Poulain S, Morel P et al. Increased trisomy 12 frequency and a biased IgVH 3–21 gene usage characterize small lymphocytic lymphoma . Leuk Res 2009 published on line doi:10.1016/j.leukres.2009.11.003 Accessed 30th January 2010.

5. Morrison W, Hoppe R, Weiss L, et al. Small lymphocytic lymphoma. J Clin Oncol 1989; 7:598–606.



Take-home points:

Terry, you can see from the lively discussion below how very much our members appreciated your article.  With your permission I would like to summarize what we have learned.  For those of our readers who are not members and therefore shut out of the discussions, I have decided to add this recap to the end of your article.

  1. SLL is less common than CLL – about 10% of patients are originally diagnosed with SLL.
  2. SLL has the same morphology as CLL, which is why the IWCLL calls them both the same disease.  The same prognostic indicators are still relevant (IgVH gene mutation status, FISH, CD38, ZAP70), the same “risk bucket” definitions still apply.
  3. It makes more sense to use the Ann Arbor lymphoma staging system (see link above in main article) rather than the more familiar Rai or Binet staging systems since SLL is a lymphoma and not a leukemia – this is particularly true in early stage SLL.  Late stage SLL looks a lot like CLL and the distinctions in staging systems become moot.
  4. Early stage SLL is defined as having enlarged lymph nodes; red blood cell, platelet and neutrophil counts all in the normal ranges, and peripheral blood ALC less than 5.0K. Bone marrow infiltration should be low, less than 30% according to some experts (but this is still a controversial cut-off point). In other words, except for a couple of pesky swollen lymph nodes everything else should look perfectly normal.
  5. When SLL progresses to later stages it gradually involves more and more of the lymph nodes, starts spilling over into the blood (you will see increased WBC, ALC) and infiltrates the bone marrow.  At this point, distinctions between SLL and CLL disappear for all practical purposes.  Late stage SLL and CLL are treated exactly the same way, same decision points of when to start therapy and what to use for frontline therapy etc.  Late stage SLL and CLL are the same beast, no difference.
  6. Here is the most important take-home message as I understood it.  Early stage SLL, while it is still restricted to just a few swollen lymph nodes, before it has spread to the rest of the lymph nodes, blood and bone marrow, presents patients with a chance of possible CURE – by judicious use of targeted radiation therapy. 
  7. Think of it this way.  Early stage SLL is localized to a few lymph nodes only, we can hit it hard with radiation just as we can any localized lymphoma or solid cancer.  Radiation therapy has its own risks and toxicity but which of us would sneeze at the risks of radiation when weighed against the rewards of a possibly full CURE?
  8. Compared to early stage SLL, equally early stage CLL does not give us the option of targeted radiotherapy since CLL is not localized to just a couple of locations.  CLL is a leukemia;  its home is the blood.  From day one, CLL is present everywhere blood is present, that means everywhere in your body.
  9.  The problem with correct treatment of SLL seems to be one of (a) understanding the nature of early stage SLL, that in its infancy it marches to a different drum beat than early stage CLL (b) confirming the localized nature of the SLL while  it is still in early stage (c) having the expertise to know that early stage SLL is treatable and perhaps curable with targeted radiation.
  10. As you can see, detection and monitoring of swollen lymph nodes is a whole lot more important in early stage SLL than CLL. This is especially so if you want to take advantage of the window of opportunity presented in early stage SLL: a chance to possibly get rid of the disease once and for all and hit a home run CURE. The single best method for detecting and accurately measuring the size of lymph nodes buried deep in your abdomen is CT scan with contrast.  MRI leaves the picture a bit fuzzy. PET scans are not as definitive either.
  11.  Bottom line, if you have just been diagnosed with SLL and you fit the profile described above for early stage SLL, you have some decisions to make. Will you take the conventional wisdom of Watch & Wait prescribed to all CLL patients, or will you make a push for detailed evaluation of your disease status (number, size and location of your lymph nodes, level of bone marrow involvement, ALC and other blood counts) and see if you are a good candidate for targeted radiation therapy that may be able to get this monkey off your back once and for all?
  12. This decision is time sensitive. If you wait too long and your SLL has gradually spilled over into more and more lymph nodes, the blood and bone marrow, at that point you are no different than any other late stage CLL patient. It is no longer possible to do targeted radiation with an intention to cure.  Targeted radiation may still be possible to reduce a particular pesky node that is interfering with some essential body function, but that is a different kettle of fish.