Waldenstroms Macroglobulinemia WM

Definition (JCO 2005:23:1564)

• Low-grade NHL (lymphoplasmacytic lymphoma) that secretes IgM

• No evidence of bone lesions (IgM M component • lytic bone lesions "IgM myeloma") Clinical manifestations

• Tumor infiltration: BM (cytopenias). hepatomegaly, splenomegaly, lymphadenopathy

• Circulating IgM

hyperviscosity syndrome (15%)

neurologic blurred vision ("sausage" retinal veins on funduscopy). HA. dizziness. A MS cardiac: congestive heart failure pulmonary: pulmonary infiltrates type I cryoglobulinemia — Raynaud's phenomenon anemia (prominent rouleaux; 10% Coombs' © AIHA) mucosal bleeding due to abnormalities in platelet fxn ^^s. • IgM deposition peripheral neuropathy: may be due to IgM against myelin-associated glycoprotein amyloidosis glomerulopathy

Diagnostic evaluation

• SPEP ♦ immunofixation with IgM >3 g dl; only 20% have © UPEP

• Bone marrow biopsy: t plasmacytoid lymphocytes

' Relative serum viscosity: defined as ratio of viscosity of serum to H2O (normal ratio 1.8) hyperviscosity syndrome when relative serum viscosity >5-6


• Hyperviscosity: plasmapheresis

• Symptoms: systemic chemotherapy with chlorambucil, fludarabine. cladribine. rituximab.

or combination therapy

• Thalidomide and HSCT are Investigational modalities


Transplantation of donor pluripotent cells that can reconstitute all recipient blood lineages



Donor-recipient relationship

of Stem Cell Transplantation

Allogeneic (Alio) Autologous (Auto)

Immunologically distinct Donor is also recipient

Graft-versus-host disease



Graft-versus-tumor effect



Risk of graft contam. w tumor



Relapse risk (leukemia)



Transplant-related mortality



• Graft-versus-host disease (GVHD): undesirable side effect of alio HSCT

allogeneic T cells view host cells as foreign; î incid. w mismatch or unrelated donors need post-transplant immunosuppression

• Graft-versus-tumor (GVT) effect: desirable consequence of alio HSCT;

allogeneic T cells attack host tumor cells

I Indications (NEJM 2006;3S4:1813)

• Malignant disease:

Auto HSCT allows higher doses of chemo by rescuing hematopoietic system (used for lymphoma, multiple myeloma, testicular cancer) Alio HSCT produces graft-versus-tumor (GVT) effect, in addition to hematopoietic rescue (used for AML.ALL. CML CLL. MDS. lymphoma)

• Nonmalignant disease: alio HSCT replaces abnormal lymphohematopoietic system with one from normal donor (eg. immunodeficiencies, aplastic anemia. i hemoglobinopathies, possibly autoimmune disorders)

Transplantation procedure

• Preparative regimen: eradication of dseose for which transplant is being performed and immunosuppression to prevent rejection of transplanted graft (alio only) myeloablative (traditional): chemotherapy and or total body irradiation nonmyeloablative: low-intensity conditioning regimens i toxicity to allow Pts w comorbidities or older Pts to tolerate HSCT. Allows mixed chimeric state in an attempt to temper GVHD while harnessing GVT effect.

bone marrow: original source, most experience peripheral blood stem cells (PBSC): faster engraftment. easier collection umbilical cord blood: less stringent HLA-matching requirements, though fewer available cells from donor (multiple donors can be combined), slower engraftment

• Absolute neutrophil count (ANC) recovers to 500 p.1 w in 3 wks w BM and

2 wks w PBSC. G-CSF accelerates recovery by 3-5 d in both scenarios. Complications

• Either direct chemoradiotoxicites associated with preparative regimen or consequences of interaction between donor and recipient immune systems

Timing and Mechanism of Noninfectious Complications of HSCT


<30 d

30-90 d

>90 d



Growth failure


Mucositis, rash, alopecia

Hypogonadism infertility

Nausea, vomiting, diarrhea


Peripheral neuropathies


Hemorrhagic cystitis

Avascular necrosis of bone

Veno-occlusive disease

Second malignancy

Interstitial pneumonitis


Acute GVHD

Chronic GVHD


Primary graft failure

Secondary graft failure

Sinusoidal obstruction syndrome (SOS; incidence 10%. mortality 30%) Previously known as veno-occlusive disease (VOD)

Mech: direct cytotoxic injury to hepatic venules - in situ thrombosis Symptoms, tender hepatomegaly, ascites, jaundice, fluid retention with severe disease . liver failure, encephalopathy, hepatorenal syndrome Diagnosis:' ALT AST. T bilirubin: T PT with severe disease; Doppler U S may show reversal of portal vein flow; t hepatic wedge pressure: abnl liver bx Treatment: supportive; prophylaxis with ursodiol or low-dose heparin; defibrotide Idiopathic interstitial pneumonitis (IIP. up to 70% mortality) Mech: alveolar injury due to direct toxicity — fever, hypoxia, diffuse pulmonary infiltrates Diffuse alveolar hemorrhage (DAH): subset of IIP

Diagnosis: bronchoscopy to exclude infection; i bloody lavage fluid seen with DAH Treatment: high-dose corticosteroids (limited data) Acute GVHD (within 3 mos of transplant) Clinical grade l-IV based on scores for skin (severity of maculopapular rash), liver

(bilirubin level), and Gl (volume of diarrhea); bx supports diagnosis Prevention: immunosuppression (MTX • CsA or tacrolimus) • T-cell depletion of graft Treatment: grade I none: grade ll-IV-associated with J survival and . . treated with immunosuppressants (corticosteroids. CsA. tacrolimus, rapamycin. rituximab) Chronic GVHD (developing or persisting beyond 3 mos posttransplant) Clinical: malar rash, sicca syndrome, arthritis, obliterative bronchiolitis, bile duct degeneration and cholestasis Treatment: immunosuppressants as above; photopheresis Graft failure

Primary persistent neutropenia without evidence of engraftment Secondary delayed pancytopenia after initial engraftment; either immune mediated due to attack by immunocompetent host cells in the allogeneic setting (termed graft rejection) or non-immune mediated (eg. CMV infection) Infectious complications due to regimen-induced pancytopenia and immunosuppression auto HSCT recipients do not require immunosuppression and remain at t risk only during the pre-engraftment and immediate postengraftment phases both primary infections and reactivation events occur (eg. CMV. HSV. VZV)

Infectious Complications Following Allogeneic HSCT

Time after transplant and associated risk factors

Class of pathogen and associated prophylaxis

Days 0-30 Days 30-90

Mucositis Acute GVHD Organ dysfunction i cellular Neutropenia immunity

>90 days

Chronic GVHD 4 cellular & humoral immunity

Viral acyclovir to d 365 (HSV VZV);

Respiratory and enteral viruses

HSV CMV. HHV 6 & 7

valgancidovir or ganciclovir if CMV • (monitor until d 100 or until no longer immunesupp.)

EBV-related lymphoma

Gram © cocci (coagulase-negative staph., S. aureus, S. vindans) GNRs (Enterobacteriaceoe, Pseudomonas. Legionella. S. maltophilia)


Bacterial antibiotics (eg. fluoroquinolone) while neutropenic

Encapsulated bacteria

Fungal fluconazole to d 75 for Candida

Candida spp.

Aspergillus spp.


T. gondii

T. gondii

TMP-SMX to d 180 (or off

P. carinii

P. carinii

immunosuppression) for PCP

S. stercoralis

'Primarily among persons who are seropositive before transplant

'Primarily among persons who are seropositive before transplant

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