Session Five: Case Histories
The physician-presenters were assembled in a panel for this session. Six actual case histories, with identities removed, were presented one by one. As each case was set forth, the members of the panel were asked to indicate which of several suggested therapies would, in their individual opinions, be most likely to produce remission or otherwise alleviate the patient's condition. In no case was there unanimous agreement. Case histories are reported verbatim as presented.

Case No. 1
Waldenstrom's macroglobulinemia:
Asymptomatic patient with rising IgM levels
This 69 year old female was diagnosed with Waldenstrom's macroglobulinemia 3 years ago after presenting to her primary care doctor for a routine physical examination. She was noted at that time to have a high sedimentation rate (100 mm/hr), anemia (hematocrit of 33), an elevated total protein (7.3) which lead (sic) to a referral to a hematologist and the diagnosis of WM. Her IgM at the time of diagnosis was 2010 mg/dL; her platelet and white blood counts, beta2M, and serum viscosity were normal. The patient was observed closely and was noted to have a continual rise in her IgM though she remained asymptomatic. In the Fall of 2001, her IgM level was noted to be 6,050 mg/dL, with a serum viscosity level of 2.9 CP, beta2M of 2.9, hematocrit of 33, platelets of 275,000 and white blood count of 7.4. Bone marrow biopsy demonstrated 70% involvement with tumor cells which were CD19+, CD20+, CD5-, CD23-, consistent with the diagnosis of WM. The patient remains asymptomatic. What do you recommend at this point?

1. Initiate therapy with Fludarabine or Cladribine.
2. Initiate therapy with Chlorambucil alone or with prednisone.
3. Initiate therapy with Rituximab alone or in combination with other drugs.
4. Initiate therapy with combination chemotherapy (CHOP, CVP, COP).
5. Initiate therapy with Thalidomide alone or in combination with other drugs.
6. High dose chemotherapy with an autologous stem cell transplant.
7. Do not initiate therapy. Continue close observation of patient. Consider initiating therapy when the patient becomes symptomatic or has worsening anemia or hyperviscosity.
8. Other.
The consensus of the panel was to continue watch-and-wait, meanwhile looking for available clinical trials, since treatment seemed necessary in the not-too-distant future. If treatment were initiated now, it should be something relatively non-toxic like Rituxan.

Case No. 2
Waldenstrom's macroglobulinemia:
Elderly patient with anemia.
A 78 year old female presented to the hospital with profound fatigue and shortness of breath with mild exertion which considerably limited her daily activities of life. The patient was noted to be anemic with a hematocrit of 26. Her WBC was 3,000 and platelet count was 190,000. Further workup demonstrated that the patient was not bleeding nor was she experiencing blood loss on the basis of any hemolysis (red cell destruction). Additional laboratories showed that the patient had an IgM monoclonal spike with a total IgM level of 2,380 md/dL. Her beta2M was 4.0, and serum viscosity was 1.8. The patient was transfused with one unit of packed red blood cells and was initiated on erythropoietin (PROCRIT) at 40,000 units per week. She had a transient rise in her hematocrit following the transfusion but remained in the 27-28 range while on erythropoietin and continued to have fatigue and shortness of breath with mild exertion. What therapy would you recommend for this patient?

1. No therapy. Continue supporting the patient with red blood cell transfusions as needed.
2. Chlorambucil alone or with Prednisone.
3. Monoclonal antibody therapy (Rituximab).
4. Nucleoside analogue therapy (Fludarabine or Cladribine).
5. Combination chemotherapy (CHOP, CVP. COP).
6. Other.
In the course of the discussion it was further revealed that the bone marrow involvement in the patient was seventy percent (70%). The majority of the panel opted for rituximab therapy, with nucleoside analogues as an alternative. The patient, of course, should be involved in the decision, but the general feeling was that a hematocrit below thirty (30) demanded treatment. Dr. Frankel revealed that he would never use nucleoside analogues alone, always in combination with rituximab to increase their effectiveness.

Case No. 3
Waldenstrom's Macroglobulinemia:
Newly diagnosed patient with neuropathy.
A 41 year old man presented to his primary doctor with bilateral lower extremity numbness, and fatigue. A complete blood count was obtained that revealed the patient was moderately anemic (hematocrit of 29). A serum immunoelectrophoresis was obtained that revealed an elevated serum IgM (1,800 mg/dl) with an IgM kappa monoclonal spike, beta2M of 4.0 and serum viscosity level of 1.9 CP. A bone marrow biopsy revealed 60% involvement with lymphoplasmacytic cells that were CD19+, CD20+, CD5-, CD10-, CD23- consistent with the diagnosis of WM. Anti-myelin associated glycoprotein (anti-MAG) titers were strongly positive. The patient has no siblings.
What is the best option for this patient at this time:
1. Plasmapheresis as needed.
2. Chlorambucil with or without prednisone.
3. Nucleoside analogue therapy (Fludarabine or Cladribine) alone or in combination with other drugs.
4. Monoclonal antibody therapy (Rituxan).
5. Combination chemotherapy (CVP, CHOP, COP).
6. High dose chemotherapy with autologous stem cell transplant.
7. High dose chemotherapy with allogeneic stem cell transplant if identical match available.
8. Other
The reaction seemed to be that plasmapheresis should be used to give immediate relief, aided perhaps by Rituxan therapy. Another possible choice would be Cytoxan. Care must be taken to avoid as much as possible damage to the immune system, to keep open the option of transplant, whether with his own or another's stem cells, in the future.

Case No. 4
Waldenstrom's macroglobulinemia:
Presentation with Hyperviscosity Syndrome and Complications of Therapy

A 56 year old male presented to his primary care doctor with fatigue, headache and visual disturbances. Fundiscopic examination revealed retinal hemorrhaging. Laboratory studies were as follows:
Hematocrit 26%; Platelet count 90,000; White Blood Count 3,100
Total IgM: 8,300 mg/dL
Serum viscosity 6.8 CP
Bone marrow biopsy: 80% involvement of core by CD19+ CD20+ CD5- CD23-lymphoplasmacytic appearing cells.
The patient underwent emergency plasmapheresis with a much improved serum viscosity and resolution of symptoms. What is the most appropriate therapy for this patient?
1. Observation, and additional plasmapheresis as needed.
2. Initiate therapy with Fludarabine or Cladribine.
3. Initiate therapy with Chlorambucil alone or with prednisone.
4. Initiate combination chemotherapy (CHOP, CVP, COP).
5. Initiate therapy with a monoclonal antibody (Rituximab).
6. High dose chemotherapy and autologous stem cell transplant.
7. Other.
The patient received chlorambucil and prednisone for the next 6 months. His blood counts improved modestly, but his IgM began to climb despite therapy. He subsequently received 4 courses of Fludarabine (25 mg/m2 qD X 5 days) with a decrease in his IgM to 2,200 mg/dL, and improved blood counts. Seven months later the patient began to experience gait abnormalities, and somnolence. An MRI was obtained which showed extensive CNS demyelination. The patient's blood counts began to deteriorate and his IgM began to climb.

The best course of treatment for this patient at this time is:
1. Additional courses of Fludarabine.
2. Monoclonal antibody therapy (Rituximab).
3. Thalidomide alone or in combination with other drugs
4. High dose chemotherapy with autologous stem cell transplant.
5. Mini allogeneic transplant.
6. Other.
The panel was all over the lot on this one, particularly after it was pointed out through a brain scan slide that the patient showed the white-blotch symptoms of PML (progressive multifocal leukoencephalopathy, a usually fatal viral brain disease). Presumably the normal blood-brain barrier had been breached, and the chemotherapy had wreaked havoc there, though there are no studies proving that connection or the level of brain damage chemotherapeutic agents of the kind used in WM might cause, so the disease could be unrelated.
Proposals ranged from stem cell transplant to "hospice and comfort." All were relieved to learn that the patient had received rituximab, was much recovered, and had even tried to register for the conference, unsuccessfully because the meeting was already fully subscribed. Here, it was observed, is a case which very clearly demonstrates that we are unclear on the real nature of WM and on the best treatments.

Case No. 5
Lymphoplasmacytic Lymphoma:
Refractory disease in a young patient
This 42 year old mother of two young children presented to her primary care doctor with multiple hive-like lesions on her forearms and legs, along with profound fatigue, and night sweats. She was noted to have an elevated B2M, IgG level of 5,030 mg/dL, serum viscosity of 2.3 CP, and a hematocrit of 29.2. CT scans were unremarkable. Bone marrow biopsy revealed 80% involvement with lymphoplasmacytic cells which were CD19+, CD20+, CD5-, CD10-, CD23-. A biopsy of one of the skin lesions revealed cellular urticaria (hives) and raised the finding of Schnitzler's syndrome (hives associated with fever, bone pain, and a concentration of IgM. Extremely rare -- only about 50 cases can be found in the literature). The patient was treated with CHOP-Rituxan and had resolution of her symptoms and skin lesions after 2 cycles and a decrease in her IgG level to 2,930 mg/dL was noted. However, by the end of the 3rd cycle of CHOP, her symptoms and skin lesions recurred and her IgG rose to 4,420 mg/dL. The patient was then begun on Cladribine (2-CDA), and received 2 cycles of therapy with little benefit. She subsequently received Thalidomide and Dexamethasone which resulted in a minor response lasting for four months, following which the patient's disease again began to progress. Repeat bone marrow biopsy showed 60-70% involvement with CD20+, CD52+ tumor cells. She has no HLA matched siblings, and a 5/6 match through the NBMT registry. At this point what do you recommend?
1. Chlorambucil alone or with prednisone.
2. Salvage chemotherapy (ESHAP, ICE) followed by high dose chemotherapy and autologous stem cell transplantation.
3. High dose chemotherapy and allogeneic transplantation.
4. Mini allogeneic transplantation.
5. Monoclonal antibody therapy (Campath-1H).
6. Radioimmunotherapy (Zevalin).
7. Other.
The general opinion was that this case required salvage chemotherapy followed by a transplant, either autologous or allogeneic to be decided as the case progressed. What was in fact used by the attending physician was Campath, with the understanding that she will eventually need transplantation. This was done with caution, because Campath can be toxic.

Case No. 6
Waldenstrom's macroglobulinemia:
Patient with a second relapse of disease.
This 53 year old male was diagnosed with WM in 5/98 after he presented to his physician with fatigue and recurrent nose bleeds. He was noted to have an IgM level of 4,800 mg/dL, viscosity level of 7.9 CP, moderate anemia (Hematocrit of 30) and a beta2M of 4.7. The patient was treated with 6 cycles of Fludarabine and Mitoxantrone, which resulted in a partial remission lasting for almost one year, with an IgM nadir of 1590 mg/dL, and a viscosity level of 2.0. Subsequently, his IgM level began to climb and he began to re-experience fatigue, along with sensory neuropathies involving his upper and lower extremities. He received 8 infusions of Rituximab which he completed in September of 2000, with notable symptomatic improvement and a decrease in his IgM from 3,160 to 2,250 mg/dL. His IgM continued to drop and reached a nadir nine months later at 1,360 mg/dL following which he received 4 more infusions of Rituximab as maintenance therapy. Six months later, the patient's symptoms began to progress and his IgM has climbed to 3,600 mg/dL and serum viscosity level to 2.7 CP. Repeat bone marrow biopsy shows WM tumor cells (CD20+, CD52+) with 60% BM involvement, and his CT scans are negative. He has no siblings, and a 5/6 HLA match. At this point what therapy do you recommend?
1. Additional infusions of Rituximab.
2. Additional infusions of Fludarabine or Cladribine (alone or with other drugs).
3. Combination chemotherapy (CHOP, CVP, COP).
4. Thalidomide alone or in combination.
5. Monoclonal antibody therapy with Campath-1H.
6. Monoclonal antibody therapy with Zevalin.
7. High dose chemotherapy with autologous stem cell transplant.
8. High dose chemotherapy with allogeneic stem cell transplant.
9. Mini allogeneic transplant.
10. Other therapy.
It was generally agreed that some sort of transplant was in the cards for this patient. But for the present he might be well served by a rituximab-fludarabine combination to clean things up temporarily. Rituxan used alone might be easier on the system if stem cell harvest were to be tried.

Discussion

Questions were raised concerning the use of alkylating agents as opposed to purine analogues. It was generally agreed that nucleoside purine analogues gave a better quality of life to the patient. However, there does not seem to be much difference in the length of average survival.
While there are no final answers, there are certain no-brainers.
A. Consider all the options of therapy available to you. Be an active part of the decision-making process.
B. Always get a second opinion; two heads are better than one.
C. Do what you feel comfortable with. The patient, after all, is the real center here. Do what you think is best for you and will give you the best quality of life, not just the longest stretch of time.
D. Participate in clinical trials if they are available to and appropriate for you. Trials are, after all, the only way to advance our knowledge of WM.
E. Lobby for greater government attention to WM. Keep WM in front of the governmental money providers.

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