Long-term risk of myelodysplasia in melphalan-treated patients with immunoglobulin light-chain amyloidosis

Survival of patients with plasma cell disorders has increased.However, the expanding use of melphalan in patients with longersurvival suggests that myelodysplasia may become increasinglyimportant. The objective of this study was to determine therisk of myelodysplasia after treatment with melphalan for patientswith amyloidosis. We reviewed the long-term follow-up data (morethan 12 years) from 101 patients with immunoglobulin light-chainamyloidosis. We identified 10 patients with myelodysplasia oracute nonlymphocytic leukemia that directly caused death for8 and transfusion dependency for 2. Two of the 10 patients didnot have development of myelodysplasia until 144 months afterfirst exposure to alkylating agents. The actuarial risk of myelodysplasiadevelopment at ten years was 18%. As the survival of patientswith plasma cell disorders improves, myelodysplasia may be amore common cause of morbidity and mortality for this group.

Key words: acute nonlymphocytic leukemia, amyloidosis, immunoglobulin light chain, melphalan, myelodysplasia.

Introduction

TOP

Introduction

For more than 30 years, the risk of alkylator-induced myelodysplasiahas been well recognized in the treatment of hematologic malignancies.¹Previously, melphalan was the only treatment available for patientswith myeloma and amyloidosis, even though it was known to bea direct cause of myelodysplasia.^2,3 However, because the mediansurvival was three years for patients with multiple myelomaand 18 months for those with amyloidosis, the number of patientsat risk for this devastating, late complication was small.

Use of melphalan declined substantially with the advent of stemcell transplantation, which carries a low risk (approximately2%) of clinical myelodysplasia.⁴ Moreover, a shift in treatmentin the late 1980s emphasized corticosteroid-based combinationssuch as dexamethasone, thalidomide-dexamethasone, and vincristine-doxorubicin-dexamethasone;all were effective and spared patients from exposure to alkylatingagents.⁵ Nevertheless, the use of melphalan for myeloma andamyloidosis began to increase. The combination of melphalanand high-dose dexamethasone was reported as an effective regimenfor patients with immunoglobulin light-chain amyloidosis whowere ineligible for stem cell transplantation,⁶ and responserates were similar to those of stem cell transplantation. A5-year update confirmed the results and showed that they weredurable.⁷ A subsequent phase 3 trial⁸ suggested that outcomesof patients with amyloidosis treated with melphalan-dexamethasonewere equivalent to those treated with high-dose melphalan therapyplus autologous stem cell transplantation. These results launchedthe increasing use of oral melphalan for the management of patientswith amyloidosis.

Melphalan-prednisone-thalidomide treatment is increasingly consideredas an option for elderly patients with multiple myeloma,⁹ andsimilar results have been observed after using a combinationof melphalan, prednisone, and borte-zomib.¹⁰ Thus, melphalanuse will likely be more common in the management of patientswith multiple myeloma, and complications of melphalan shouldbe expected with greater frequency.

Because the development of myelodysplasia is a time-dependentphenomenon, long-term follow-up is required to ensure that allpatient data are captured. In this report, we describe morethan 12 years of follow-up data from a uniformly treated cohortof patients and detail the high incidence of myelodysplasia.

Design and Methods

TOP

Design and Methods

All patients in this study have been described previously¹¹;however, the earlier publication reported only the responseto therapy and survival as an end point. All patients providedwritten, informed consent before study entry, and the originalprotocol and this current review were both independently approvedby the Mayo Clinic Institutional Review Board. Amyloidosis wasconfirmed histologically, and all eligible patients had a clinicallydetectable amyloidosis syndrome such as cardiomyopathy, nephroticrange proteinuria, peripheral or autonomic neuropathy, unexplainedhepatomegaly, or debilitating soft tissue involvement. All patientswere previously untreated. At study entry, patients had a granulocytecount greater than 0.75x10⁹/L and a platelet count greater than50x10⁹/L. Patients with overt multiple myeloma or secondary,familial, or localized amyloidosis were ineligible for the study.

For the patients assigned to the melphalan-prednisone treatmentarm, 1.05 mg/kg of melphalan was administered orally with every6-week cycle (dosage was divided over seven days). Prednisonewas administered orally for the same seven days (dosage, 0.8mg/kg). Patients in the second treatment arm of this study weretreated with melphalan, carmustine, cyclophosphamide, vincristine,and prednisone. The melphalan dosage in this protocol was 8mg/m², administered orally for four days. The carmustine dosagewas 20 mg/m² on day 1, and the cyclophosphamide dosage (administeredparenterally) was 400 mg/m² on day 1. The vincristine dosagewas 14 mg/m² (administered intravenously) on day 1, and theprednisone dosage was 40 mg/m² (administered orally) for fourdays. Treatment was repeated every six weeks. For both studyarms, the goal was 18 cycles of treatment unless serious complicationsof toxicity developed that warranted cessation of therapy. Dosageswere modified during treatment for thrombocytopenia, neutropenia,and renal insufficiency. The total amount of administered melphalanwas approximately 20% lower in the group randomized to receivevincristine, carmustine, melphalan, cyclophosphamide, and prednisone.

Development of myelodysplasia was previously defined as bonemarrow morphology consistent with dysplasia.¹² Patients hada reduction of neutrophils, platelets, or hemoglobin that wascompatible with the dysplastic changes of the marrow. Bone marrowbiopsies were not performed routinely during this study; theywere performed after cytopenia was recognized and only if clinicallyindicated.

All patients were prospectively entered into a database, andlong-term, follow-up data have been gathered since the studywas initiated in August 1991. No patients were subsequentlyexcluded, and none were lost to follow-up. Comparisons of patientswith and without development of myelodysplasia were performedusing nonparametric statistics; we used 2x2 contingency tablesfor nominal variables (Fisher exact test) and Wilcoxon ranksum test for continuous variables. Actuarial assessment of timeto development of myelodysplasia was performed using Kaplan-Meiermethods. All p values were 2-sided.

Results and Discussion

TOP

Results and Discussion

At least one cycle of melphalan-based chemotherapy was administeredto 101 patients. As of the publication of this report, 89 patientshave died, and 12 are actively monitored. Of the 12 survivors,the minimum follow-up period was 12.5 years. Table 1 shows patientcharacteristics stratified by myelodysplasia development (10patients had myelodysplasia, 91 did not).

View this table:
[in this window]
[in a new window]
[Download PPT slide]
Table 1. Patients’ characteristics.

As previously shown,¹³ age was a risk factor for developmentof myelodysplasia in melphalan-exposed patients (median agedifference, eight years). Patients with cardiac amyloidosishad a reduced incidence of myelodysplasia. This finding wasunsurprising because myelodysplasia, a time-dependent variable,did not develop in any patient until 14 months after treatment,and 28 of the 51 patients with cardiac amyloidosis died within14 months after treatment. Thus, the competing risk of deathfor patients with cardiac amyloidosis reduced the risk of myelodysplasiadevelopment. Furthermore, patients without myelodysplasia generallyhad greater interventricular septal thickness than patientswith myelodysplasia; this finding was consistent with the group’shigher mortality rate (due to cardiac complications), and theshortened survival thereby precluded myelodysplasia development.In contrast, patients with peripheral nerve amyloidosis havemuch longer survival than patients without peripheral nerveinvolvement¹⁴ (in our cohort, 8 out of 11 with nerve amyloidosissurvived longer than 14 months), and this group therefore hada disproportionately higher risk for development of late complications.

Table 2 provides specific characteristics of the 10 patientswith myelodysplasia. Six of the 10 had classic abnormalitiesof chromosome 7. The one patient with a normal karyotype hadclassical morphological marrow features of myelodysplasia. Allpatients had neutropenia, and all had a platelet count lessthan 0.15x10⁹/L. The median time for disease development was58 months, but we note that 2 patients did not show evidenceof myelodysplasia until 144 months after their initial exposureto melphalan. The median survival after establishing the myelodysplasiadiagnosis was 6.5 months. The overall survival of the 10 patientsafter study enrollment was 55 months, which was substantiallygreater than the survival of patients without myelodysplasia(22 months). However, these results were skewed because patientshad to survive long enough for myelodysplasia to develop.

View this table:
[in this window]
[in a new window]
[Download PPT slide]
Table 2. Characteristics of patients with myelodysplasia.

As noted in Table 2, myelodysplasia or acute nonlym-phocyticleukemia was the direct cause of death in 6 patients. A seventhpatient underwent allogeneic bone marrow transplantation (withfull-intensity conditioning) and died of a transplantation-relatedcomplication. An eighth patient was receiving concurrent dialysistreatment, and the direct cause of death (dialysis vs. dysplasia)could not be determined. The one surviving patient is transfusion-dependent(hemoglobin, 9.9 g/dL; mean corpuscular volume, 112.5 fL; neutrophils,0.9x10⁹/L). Figure 1 shows the actuarial risk of myelodysplasiadevelopment: at 10 years, the risk was 18%, and at 12 years,the risk was 30%.

View larger version (8K):
[in this window]
[in a new window]
[Download PPT slide]
Figure 1. Actuarial risk of myelodysplasia in 110 patients with primary amyloidosis. Each tick mark represents a patient who died before myelodysplasia or acute nonlymphocytic leukemia developed.

Twenty years ago, a distinct shift occurred in the managementof patients with myeloma and amyloidosis from alkylating agentsto dexamethasone-based regimens. However, a recent study ofelderly patients with multiple myeloma reported no differencein the overall survival of those treated with melphalan andprednisone and of those treated with dexamethasone-based regimens.¹⁵These results indicated that dexamethasone need not be recommendedroutinely as first-line treatment for elderly patients. Althoughthe study had limitations (it pre-dated the introduction ofnovel agents for the treatment of myeloma and amyloidosis anddid not include the recently introduced weekly dexamethasoneschedule in the 4-arm study design), melphalan, in combinationwith novel agents, is becoming the standard treatment for patientswith myeloma over 65 years of age.^9,16 Differences in treatmentbetween patients in the study cohort and those of our currentpractice include a longer duration of chemotherapy for studypatients (18 months) compared with exposures of 6–14 monthsfor current melphalan-containing regimens. In our cohort, thepatients with development of myelodysplasia consistently receivedmore than 1,000 mg of melphalan. With current regimens, melphalandosages should not exceed 600 mg; this may have the importanteffect of reducing the risk of myelodysplasia.

The median survival of patients with amyloidosis was previouslythought to be about 18 months,¹⁷ but this changed dramaticallyto about five years with the introduction of the melphalan-dexamethasoneregimen for management⁶ and to about 41 months with the useof orally administered cyclophosphamide, thalidomide, and dexamethasone.¹⁸With improved therapy, survival periods of ten years or longerwill likely become common. With longer survival, increased exposureto melphalan may result in therapy-related acute nonlymphocyticleukemia and myelodysplasia.¹⁹ When the survival of patientswith myeloma and amyloidosis was short, late complications ofmelphalan were difficult to ascertain because the risk of deathfrom myeloma was 10-fold greater than the risk of a treatment-relatedcomplication.²⁰ As therapies become more effective and patientslive longer, the risks may change. Our study shows that theoverall risk of myelodysplasia development was 10%, but theactuarial risk rose from 18% at ten years to 30% by 12 years.

Other studies may underestimate the risk of late myelodysplasiabecause many only report the response to therapy and relapse-freesurvival rate and lack prolonged follow-up data. Late riskscannot be estimated accurately by using reports with medianfollow-up periods of approximately five years. In our studycohort, a more accurate appraisal of the risk of alkylatingagents can be made because we lost no patients to follow-upand had a minimum follow-up period of 12 years for the survivors.

Because of the low proliferative rate of plasma cells in primaryamyloidosis, metaphase cytogenetic data are usually uninformative.Standard cytogenetic analysis was performed in 21 patients withprimary amyloidosis, and adequate metaphase results were obtainedin 20 (95%). Results were normal in 18. In one patient, thesole abnormality was absence of chromosome Y. In another patientwho had previously been exposed to alkylator therapy, 46,XX,+der(1;7)(q10;p10),–7[10]/46,XX was found but likely was not reflective of the plasmacell clone.²¹ When chromosome damage is identified after melphalantherapy, it localizes to myeloid but not plasma cells (as shownby fluorescence in situ hybridization and immunofluorescentcytoplasmic light-chain staining).²² IgH translocations areusually observed, most commonly t(11;14)(q13;q32).²³ Patientswith primary amyloidosis do not appear to have an intrinsicpredisposition to development of myelodysplasia.

Stem cell transplantation remains an effective regimen, witha 1–2% treatment-related mortality rate in myeloma anda 10–15% rate in primary amyloidosis. The risk of clinicalmyelodysplasia is 2%.⁴ For patients ineligible for transplantation,prolonged exposure to alkylating agents may result in an overallrisk of 10% for myelodysplasia and an actuarial risk of 18%.Clearly, knowledge of these risks will not alter the managementof patients with myeloma and amyloidosis, but clinicians shouldremember to discuss the possibility of treatment-related laterisks with patients so that fully informed decisions can bemade. Redevelopment of this previously recognized complicationmay occur in the future.

Footnotes

Authorship and Disclosures

MAG: conception and design, acquisition of data, analysis andinterpretation of data; MQL, JAL, PRG, TEW, RAK: acquisition,analysis and interpretation of data. The authors reported nopotential conflicts of interest.

Received for publication February 28, 2008. Revision received April 16, 2008. Accepted for publication May 22, 2008.

References

TOP