Page 1619 - Hematology_ Basic Principles and Practice ( PDFDrive )

1440 Part VII Hematologic Malignancies

been reported. In patients with amyloidosis, lenalidomide has been cohort of patients with advanced cardiac amyloidosis, the median
reported to worsen renal function even in patients whose amyloidosis overall survival was 7 months with a 2-year overall survival of 29%.
spares the kidney. Recovery of renal function was reported in 44%. As is typical for this disease, 42% of patients died before their first
Lenalidomide salvage therapy after bortezomib achieves a hematologic response evaluation, and the overall hematologic response rate was
response rate of 41%. Pomalidomide is a third-generation immuno- 33% (12% complete). The overall survival rate was 88% at 2 years for
modulatory drug with a toxicity profile that compares favorably with complete responders, 53% for partial responders, and 22% for non-
the other immunomodulatory drugs. In a single phase II trial, 29 responders; 45% of responders achieved an organ response. The only
patients previously treated received pomalidomide with a response rate factors predictive of survival were an NT-proBNP >8500 ng/L and
of 38%. Three-fourths of the patients were alive at 1 year, and 56% a systolic blood pressure <100 mmHg. The regimens administered
were free of disease progression. The majority of these patients had included melphalan and dexamethasone, alkylating agents thalido-
previously received stem cell transplants, bortezomib, and thalidomide, mide and dexamethasone, and bortezomib as well as lenalidomide
indicating that this immunomodulatory drug is active and capable of combinations. Although this was not a prospective trial, the overall
producing durable remissions, albeit with significant toxicity. response rate for melphalan-dexamethasone-thalidomide-bortezomib
combinations ranged from 60% to 64%. The response rate to
lenalidomide combination therapy was 41% but included only 13
Bortezomib patients. The most common regimen administered was melphalan
and dexamethasone, administered to 154 of the 286 patients evalu-
Bortezomib, which was the first proteasome inhibitor used for able for response.
the treatment of amyloidosis, has the advantage of a rapid time to
response and no modification required for renal dysfunction. In
the first phase II trial, 14 of 18 patients with relapsed refractory Stem Cell Transplant
AL amyloidosis had a hematologic response, with 16% achieving
complete response. Schedules of weekly and twice-weekly bortezomib Unlike multiple myeloma, where visceral organ function tends to
have been investigated with similar response rates and similar 1-year be normal with the exception of the kidney, and the bone marrow
progression-free survival. The weekly form of bortezomib, however, tends to be heavily involved, the converse is true in amyloidosis.
does appear to have lower rates of treatment discontinuation and In amyloidosis, the marrow shows minimal involvement, but organ
peripheral neuropathy. Bortezomib has been combined with dexa- dysfunction increases the morbidity as well as the mortality of high-
methasone with a hematologic response rate of 71%, complete in dose chemotherapy and stem cell transplant. Ablative therapy can be
25%. In previously untreated patients, bortezomib produces a com- more effective, and the response durability of patients who achieve
plete response rate of 47%, although in one study the progression- a complete response is greater in amyloidosis than it is in multiple
free survival was only 5 months and the overall survival was 18.7 myeloma, the number one indication for autologous stem cell trans-
months, raising questions about how durable these responses are. plant in the United States. Stem cell transplant is not a suitable
Bortezomib has also been combined with stem cell transplant as technique for patients with advanced cardiac disease, because these
induction therapy, as posttransplant consolidation therapy, and as patients decompensate if they develop neutropenic infection during
part of the conditioning regimen. In a report of 19 patients for the phase of maximal immunosuppression. Careful patient selection
whom bortezomib was used after stem cell transplant to deepen the becomes critical in ensuring a safe outcome for patients who undergo
response, 67% of patients achieved a complete response, with organ stem cell transplant. Over the past two decades, the treatment-related
responses in 60% using posttransplant consolidation with bortezo- mortality associated with stem cell transplant has fallen from 10% to
mib. Data from 33 national centers were combined, with 94 patients 2% because of improved supportive care and optimization of patient
having received bortezomib. A cardiac response was seen in 29% of selection. As a general guideline, it has been our experience that
patients. The NT-proBNP predicted survival. The median time to patients whose NT-proBNP is >5000 pg/mL or whose troponin T is
response was 7.5 weeks. Authors of a survey of European centers with >0.06 ng/mL have too high a mortality associated with transplant and
428 evaluable patients reported that bortezomib therapy achieved a are better managed with standard-dosage chemotherapy, as outlined in
lower difference between involved and uninvolved free light chains the previous section. Systolic blood pressure >100 mmHg is also an
at the end of therapy compared with cyclophosphamide-thalidomide- important feature reflecting sufficient diastolic compliance to improve
dexamethasone, melphalan-dexamethasone, stem cell transplant, and cardiac output during the stress of stem cell transplant. Patients who
cyclophosphamide-lenalidomide-dexamethasone. have stage III and stage IV cardiac amyloidosis are candidates for stem
Bortezomib had been combined with cyclophosphamide and cell transplant if they fulfill the other criteria outlined.
dexamethasone. In a study of 17 patients, 10 of whom were therapy- At Mayo Clinic, approximately 20% of patients with newly diag-
naive, a response rate of 94% was achieved, 71% complete. A second nosed amyloidosis are eligible for high-dose melphalan. Melphalan
2
2
cohort of 43 patients achieved a hematologic response rate of 81%, 200 mg/m and 140 mg/m can both be used, but the response rates
with 42% achieving a complete response and a 2-year progression- associated with lower-dose melphalan are decreased and may not be
free survival of 67% for newly diagnosed patients. superior to the response rates reported with standard chemotherapies.
Despite the promising published results with bortezomib, a pro- The ability of stem cell transplant to produce a durable response is
spective randomized trial conducted in Europe of bortezomib, mel- unmatched in the literature, with 43% of patients surviving 10 years
phalan, and dexamethasone (BMD) compared with melphalan and or longer. Patients with more than two organs involved are oftentimes
dexamethasone failed to show any difference in organ response rates not considered adequate candidates for stem cell transplant, but
or in progression-free or overall survival in the bortezomib-containing some judgment is warranted because patients can have very mild
regimen; yet grade 3 toxicity was seen in 27% of patients receiving involvement of three organs and be candidates, yet have advanced
BMD compared with only 12% treated with melphalan and dexa- involvement of two organs and not be candidates (Fig. 88.9). The
methasone. Moreover, day 100 all-cause mortality was 7.5% in the serum creatinine is predictive of the risk of requiring dialysis during
BMD arm and only 2.5% in the melphalan dexamethasone lenalido- the transplant, a major complication leading to serious morbidity. We
mide. The hematologic response rate was higher in the BMD arm at are disinclined to perform transplant in renal amyloid patients whose
77% vs. 52% (p = .045). A compilation of 230 patients in Europe serum creatinine is ≥1.8 mg/dL. Although age is not an absolute
who received cyclophosphamide, bortezomib, and dexamethasone criterion, additional scrutiny is warranted above the age of 65. From
showed a high level of effectiveness in low-risk amyloidosis patients January 1, 2013, through December 31, 2014, 85 amyloid patients
with an at least very good partial response rate of 56% and no deaths underwent transplants; 35 were older than 65 years of age, and 11
seen in stage I patients. were over age 70 years.
A European collaborative study of treatment outcomes in 346 As with conventional chemotherapy, hematologic response is a
patients with cardiac stage III AL amyloidosis was reported. In this predictor of survival, with complete responders having improved