Patient Encounter 1

LL, a 47-year-old male, was diagnosed with high-risk diffuse large cell B-cell non-Hodgkin's lymphoma (NHL) 12 months ago. LL had a complete response to his initial treatment of six cycles of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). LL is participating in a clinical trial and is randomized to receive a myeloablative autologous HSCT: TBI days -8 to -5, etoposide day -4, rest day -3, cyclophosphamide day -2, rest day -1, with infusion of autologous PBPC on day 0.

What nonhematologic toxicity should be monitored? How long should the patient be monitored for these toxicities?

What pharmacologic management is necessary during administration of the preparative regimen?

It is day +1, and LL has a WBC with differential of 0/mm3, ANCs 0/mm3 (0 x 109/L), platelets 30,000/mm3 (30 x 103/|L), and hemoglobin 9 g/dL (5.6 mmol/L). Renal clearance and liver function are within normal limits. Vital signs are bp 130/80, RR 18, and T 39°C (102.2°F). Medications include meropenem 2 g IV every 8 hours and filgrastim 480 mcg subcutaneously daily.

Develop a monitoring plan for LL's hematologic function. Identify your treatment goals for LL's hematologic function.

Graft-Versus-Host Disease

® GVHD is caused by the activation of donor lymphocytes, leading to immune damage to the skin, gut, and liver in the recipient. Immune-mediated destruction of tissues, a hallmark of GVHD, disrupts the integrity of protective mucosal barriers and thus provides an environment that favors the establishment of opportunistic infections.

An immunosuppressive regimen is administered to prevent GVHD in recipients of an allogeneic graft; this regimen is based on the type of preparative regimen and the source of the graft. The combination of GVHD and infectious complications are leading causes of mortality for allogeneic HSCT patients. GVHD is divided into two forms (i.e., acute and chronic) based on clinical manifestations. Traditionally, the boundary between acute and chronic GVHD was set at 100 days after HSCT; however, more recent definitions hinge upon different clinical symptoms rather than the time of on-set.29

Acute GVHD The degree of histocompatibility between donor and recipient is the most important factor associated with the development of acute GVHD. The pathophysiology for acute GVHD is a multistep phenomenon, including (a) the development of an inflammatory milieu that results from host tissue damage induced by the preparative regimen, (b) both recipient and donor antigen-presenting cells and inflammatory cytokines triggering activation of donor-derived T cells, and (c) the activated donor T cells mediate cytotoxicity through a variety of mechanisms, which leads to

tissue damage characteristic of acute GVHD.

Clinically relevant grades II to IV acute GVHD occurs in up to 30% of HLA-matched sibling grafts and 50% to 80% of HLA-mismatched sibling or HLA-identical unrelated donors. Other factors that increase the risk of acute GVHD include increasing recipient or donor age (older than 20 years), female donor to a male recipient,

and mismatches in minor histocompatibility antigens in HLA-matched transplants. T-cell depletion or receipt of an umbilical cord blood graft appears to lower the risk of acute GVHD.1

Clinical Presentation and Staging of Acute GVHD Acute GVHD must be distinguished accurately from other causes of skin, liver, or GI toxicity in the HSCT patient. Other causes of toxicities affecting the skin, liver, or GI tract may include a drug reaction or an infectious process. A staging system based on clinical criteria is used to grade acute GVHD (Fig. 98-2). The severity of organ involvement is scored on an ordinal scale from 0 (no symptoms) to IV (severe symptoms), and then an overall grade is established based on the number and extent of involved organs.

Immunosuppressive Prophylaxis of Acute GVHD GVHD is a leading cause of morbidity and mortality after allogeneic HSCT and thus, efforts have focused on preventing acute GVHD. The donor graft and preparative regimen influence the prophylactic regimen for acute GVHD, with two approaches having been taken by clinicians over time. One approach involves T-cell depletion, which was discussed more fully in the section on T-cell depletion earlier. The more common method is to use two-drug immunosuppressive therapy that typically consists of a calcineurin inhibitor (i.e., cyc-losporine or tacrolimus) with methotrexate after myeloablative HSCT and a calcineurin inhibitor with mycophenolate mofetil after nonmyeloablative HSCT.

After myeloablative conditioning, acute GVHD rates have been similar or lower with triple-drug regimens, but infectious com3p1lications are higher and overall survival is similar to that with two-drug regimens. 1 With the two-drug regimen, a short-course of low-dose methotrexate (e.g., on days +1, +3, +6, and day +11) is used and thus, can delay engraftment, increase the incidence and severity of mucositis, and cause LFT elevations. The methotrexate dose is reduced in the setting of renal or liver impairment. The calcineurin inhibitors (i.e., cyclosporine and tacrolimus) should be initiated before donor cell infusion (e.g., day -1) when used for GVHD prophylaxis. This schedule is recommended because of the known mechanism of action of cyc-losporine, which entails blocking the proliferation of cytotoxic T cells by inhibiting production of T-helper-cell-derived interleukin 2 (IL-2). Administering cyclosporine before the donor cell infusion allows inhibition of IL-2 secretion to occur before a rejection response has been initiated. Studies comparing cyclosporine and tacrolimus in combination with methotrexate have shown that tacrolimus administration is asso ciated with a lower incidence of grade II to IV acute GVHD and a similar incidence

32,33

of chronic GVHD, but variable effects on overall survival. ' Because of the mu-cosal toxicity from myeloablative preparative regimens, the calcineurin inhibitors are administered IV until the GI toxicity from a myeloablative preparative regimen has resolved (e.g., for 7-21 days). Most centers use a 1:2 to 1:3 ratio for conversion of IV to oral cyclosporine with the Neoral formulation; the ratio for tacrolimus conversion from IV to oral is often 1:4. Different conversion ratios for IV to oral regimens may be used when patients are receiving concomitant medications that affect cyto-chrome P-450 3A or p-glycoprotein; these pathways are involved in the metabolism and transport of the calcineurin inhibitors (e.g., voriconazole).

FIGURE 98-2. Clinical grading of acute GVHD. The left panel summarizes the grading of one organ system; the right panel shows the overall clinical grade. With grade I, only the skin can be involved. With more extensive involvement of the skin or involvement of liver and intestinal tract and impairment of the clinical performance status, either alone or in any combination, the severity grade advances from II to IV. (From Perkins JB, Yee GC. Hematopoietic stem cell transplantation. In: DiPiro

FIGURE 98-2. Clinical grading of acute GVHD. The left panel summarizes the grading of one organ system; the right panel shows the overall clinical grade. With grade I, only the skin can be involved. With more extensive involvement of the skin or involvement of liver and intestinal tract and impairment of the clinical performance status, either alone or in any combination, the severity grade advances from II to IV. (From Perkins JB, Yee GC. Hematopoietic stem cell transplantation. In: DiPiro

JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill;2005:2552.)

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