Page 1806 - Williams Hematology ( PDFDrive )

1780 Part XI: Malignant Lymphoid Diseases Chapter 108: Immunoglobulin Light-Chain Amyloidosis 1781

was seen in 52 percent. Lenalidomide and dexamethasone have been COURSE AND PROGNOSIS
used in amyloidosis in a fashion identical to that used for multiple mye-
loma. It is important to remember that lenalidomide can increase the In spite of the introduction of new agents, late diagnosis, particularly of
level of NT-proBNP and may actually aggravate heart failure. Addi- cardiac amyloid, remains a major barrier to improvement in the over-
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tionally, the typical dose of lenalidomide used to treat multiple myeloma all survival of patients; and despite recent improvements in survival, 40
is not well tolerated by AL patients and treatment should be initiated at a percent of patients succumb to the disease within the first year after
dose of no more than 15 mg daily. There is a high discontinuation rate of diagnosis, and this early mortality has not changed in 30 years. Patients
lenalidomide within the first three cycles. Myelosuppression, skin rash, can have a hematologic response and still die of end-organ damage
and fatigue are common. In a study of lenalidomide and dexamethasone because it is impossible to repair the tissue damage that has occurred
in patients who had failed melphalan and bortezomib, two patients died prior to diagnosis. 64,65 The prognosis in amyloidosis is determined by
prior to first-response evaluation and 50 percent experienced grade 3 two primary factors. The first is the extent of cardiac involvement, and
or greater toxicity. The hematologic response rate was 41 percent. The the second is the plasma cell burden seen in these patients. The for-
median overall survival was 14 months. Cyclophosphamide, lenalido- mer, historically measured by echocardiography, is more reproducibly
mide, and dexamethasone have been used in the treatment of amyloi- measured by the use of cardiac biomarkers. The percentage of plasma
dosis with lenalidomide at 15 mg per day and cyclophosphamide 100 cells in the marrow has an important impact on prognosis. The best
9,62
mg per day. A partial response or greater was observed in 55 percent of surrogate and the most reproducible way to measure the plasma cell
patients, with complete responses in 8 percent, organ responses in 40 burden is to look at the difference between the involved and uninvolved
percent, and a 2-year overall survival of 41 percent. Cyclophosphamide, light chains in the serum (dFLC). A four-stage prognostic model has
lenalidomide, and dexamethasone hematologic response rates ranged been developed using measurements of NT-proBNP, troponin, and
from 40 to 77 percent in three different studies. Complete responses serum free light chains. One point each is assigned for a troponin T
did not exceed 10 percent. Lenalidomide toxicity was substantial and level of 0.025 ng/mL or greater, an NT-proBNP greater than 1800 pg/
included fatigue and fluid retention. mL, and a free light chain difference of greater than 180 mg/L. This
Pomalidomide has been used with dexamethasone in relapsed provides almost four equal-size groups (if you have none of the 3 its
amyloidosis. In a population of 33 evaluable patients, the response rate stage 1; if you have 1 its stage 2; if you have 2 its stage 3 and if you
was 48 percent with a median time to response of 2 months. Organ have all 3 its stage 4) with median overall survivals of 94, 40, 14, and 6
improvement was found in 15 percent. The progression-free survival months, respectively. These serum tests are currently the standard for
was 14 months; overall survival was 28 months. 72 assessing prognosis in amyloidosis. Assessing response in amyloidosis is
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Bortezomib is highly active in the treatment of amyloidosis. The a twofold process. First, the hematologic response is assessed by deter-
combination with dexamethasone in untreated patients produces a 47 mining the reduction of the plasma cell burden and of the production
percent complete response rate, with higher responses seen in patients of precursor amyloid light chains achieved by systemic therapy. There
treated with twice-weekly bortezomib. The cardiac response rate is 29 are four classes of response: (1) complete remission defined by negative
percent. Hematologic responses are associated with cardiac response immunofixation of serum and urine and a normal immunoglobulin free
as measured by a reduction in NT-proBNP. Bortezomib also has been light-chain ratio; (2) a very good partial response that requires the dif-
used with melphalan and dexamethasone, as well as cyclophosphamide ference between involved and uninvolved serum free light chain be less
with dexamethasone. The CyBorD (cyclophosphamide, bortezomib, than 40 mg/L; (3) a partial response is defined as a 50 percent decrease
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and dexamethasone) regimen was reported by the Mayo Clinic as a ret- from baseline in the dFLC; and (4) failure to respond includes all other
rospective review of 17 patients with responses seen in 94 percent (71 patients. Light-chain assessment is not only the ideal method for mea-
percent complete, 24 percent partial) and a median time to response suring response because of the rapid decline in levels if therapy is effec-
of 2 months. In many published trials, patients with severe cardiac tive, but it is better than the intact immunoglobulin as a measure of response
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involvement were excluded; as a consequence, it is difficult to determine when both are present. Although hematologic response is the first goal,
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the efficacy of bortezomib in this difficult subgroup. In one study of 38 the purpose of therapy is preservation of organ function. Therefore, to
patients with advanced cardiac disease using reduced doses of twice- have a meaningful impact, an organ response should be seen. Current
weekly bortezomib and dexamethasone, 18 of 38 patients died during data indicate that organ response rates are directly linked to hemato-
therapy; 21 patients achieved a hematologic response after a median logic response rates; and the deeper the hematologic response, the more
of three cycles. In a series of 35 patients treated with bortezomib-dex- likely there will be an organ response. A renal response is defined as
amethasone with subsequent addition of cyclophosphamide, 86 percent a 50 percent decrease in 24-hour urine protein. The decrease must be
achieved a rapid response. A second trial of cyclophosphamide-borte- no less than 0.5 g/day without a change in serum creatinine. A 50 per-
zomib-dexamethasone resulted in hematologic responses in 68 percent cent increase in urinary protein loss to at least 1 g/day or a 25 percent
and a 1-year overall survival of 65 percent. Because bortezomib has worsening of creatinine clearance is indicative of progression. Cardiac
been reported to increase the severity of heart failure in myeloma, it is response is defined primarily by changes in the NT-proBNP. A 30 per-
clearly a concern that requires monitoring in patients. The oral protea- cent reduction in the NT-proBNP, a minimum of 300 ng/L in patients
some inhibitor MLN9708, ixazomib, is currently under investigation. whose baseline NT-proBNP is greater than 650 ng/L, constitutes a
Bortezomib and dexamethasone have been used as consolidation response. However, we have seen patients in whom fluctuations of the
therapy following stem cell transplantation. Forty patients were trans- NT-proBNP of as much as 30 percent can occur as a result of changes
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planted with risk-adapted melphalan; patients with less than a complete in diuretics or the development of superimposed pulmonary infections
response received consolidation with bortezomib-dexamethasone. that are unrelated to true changes in cardiac function; consequently,
Survivals at 12 and 24 months post treatment were 88 and 82 percent, some caution is warranted in interpreting the results. An improvement
respectively. Of the original 40 patients, 23 received consolidation, in New York Heart Association class by two stages from 4 to 2 or 3 to
and their response was enhanced in 20 (86 percent). Organ response 1 also is considered a response. Historically, echocardiography has been
occurred in 70 percent at 24 months. The use of bortezomib-dexametha- used to assess response, but interobserver variability has rendered it less
sone consolidation following stem cell transplantation can help deepen useful and echocardiography is not currently part of response criteria.
the response in patients that do not achieve a complete response. Cardiac progression constitutes a 30 percent increase in NT-proBNP, a

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