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Keywords:

  • primary solid tumors;
  • myelodysplasia;
  • acute leukemia;
  • blood and marrow transplants;
  • treatment-related mortality

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Evaluation of therapeutic outcomes and risk factors was undertaken for patients with primary solid tumors (PST) developing acute leukemia or myelodysplasia (MDS) as a second malignancy.

METHODS

In all, 131 consecutive patients presenting to a single institution with leukemia or MDS after treatment for PST with surgery or chemotherapy/radiotherapy were examined. Management of the secondary acute leukemia and MDS consisted either of intensive therapy including allogeneic blood and marrow transplants or supportive measures.

RESULTS

The time from diagnosis of PST to development of acute leukemia or MDS, the cytogenetic profile of patients, and their survival were similar irrespective of PST therapy with surgery alone or strategies involving chemotherapy and/or radiation. The median survival of all 131 patients was 10.5 months with a 5-year survival of 15.6%. Induction therapy and/or transplantation resulted in a median survival of 13.6 months and a 5-year survival of 26.6% compared with 6.5 months and 2% with supportive measures. Subset analysis of transplant recipients revealed a median survival of 17.6 months and a 37.9% 5-year survival. Despite a significantly lower recurrence rate the survival of transplant recipients was not improved secondary to a higher treatment-related mortality (TRM) rate.

CONCLUSIONS

Patients developing acute leukemia or MDS after PST demonstrated similar cytogenetic profiles and clinical outcomes independent of the type of treatment. Survival was significantly better for patients able to undergo intensive therapy compared with supportive measures. The low recurrence rate for allograft recipients was consistent with a potent antileukemic effect that may translate into a survival benefit if TRM could be reduced. Cancer 2008. © 2008 American Cancer Society.

Chemotherapy and/or radiation of patients with primary solid tumors (PSTs) may result in the later development of secondary malignancies including myelodysplastic syndromes and acute leukemia. Large studies, particularly in breast cancer,1–8 have demonstrated considerable heterogeneity in the incidence and time of occurrence. These differences are at least in part related to the administration of different chemotherapeutic agents8 and differences in their dosing.9 Some common patterns have emerged for the development of secondary hemopoietic malignancies. For instance, alkylating agents and radiotherapy are commonly associated with myelodysplasia (MDS) and acute myeloid leukemia (AML) characterized by abnormalities9 involving chromosomes 5 and 7 and occur typically after a latency period of 5–7 years.10 In contrast, the latency period after administration of anthracyclines and topoisomerase II-inhibitors is on average 2 years, and cytogenetic alterations include more likely abnormalities in 11q23 and the translocations t(8;21), t(15;17) as well as inv 16.10–16 A significant number of patients present with complex chromosomal abnormalities. There is less information about the characteristic features including cytogenetic patterns of patients developing acute lymphoblastic leukemia (ALL) as a second malignancy.

The current treatment results for patients with treatment-related secondary leukemia remain unsatisfactory.16–18 Survival data are limited and only a few studies have attempted to evaluate patients with treatment-related AML/MDS separately from patients with nontreatment-related secondary leukemia.16, 17 The poor response relates to a larger proportion of patients presenting with high-risk cytogenetics,13, 17 unresponsiveness to therapy, and increases in comorbidities that preclude the administration of intensive induction therapy. Patients able to undergo intensive induction treatment, however, appear to experience similar complete remission (CR) rates, overall survival (OS), and event-free survival (EFS) as patients presenting with de novo AML.19, 20 The outcome is predominantly determined by cytogenetic risk.16, 19, 20

The role of intensive postinduction therapy including transplantation remains unclear. Published data suggest a 20% to 40% survival at 2–5 years.21–24 Few studies compared the outcome of transplants with conservative management. A significant difference was not observed.15, 24 The majority of patients entered into these studies were diagnosed with primary MDS or secondary MDS/AML predominantly emerging from hemopoietic malignancies. Large series restricted to patients with treatment-related secondary MDS or leukemia who developed after therapy for PST are not available, particularly if their acute leukemia/MDS emerged after surgical treatment without exposure to chemotherapy and/or radiation.

A single-center retrospective study was designed to capture all patients with PST who developed MDS, AML, or ALL and presented to the leukemia and transplant program at the Princess Margaret Hospital. The study had the following 2 objectives: 1) Characterization of timing and cytogenetic phenotype of acute leukemia/MDS that had developed after surgical therapy in comparison to treatment strategies that included chemotherapy and/or radiation; and 2) Evaluation of the OS of patients treated either aggressively, including the option of an allogeneic transplant, or with supportive measures only and identification of risk factors associated with outcome.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The study was approved by the institutional Cancer Registry Access Committee (CRDAC) and Research and Ethics Board (REB). Patients presenting with MDS or leukemia after therapy for PST to the leukemia service at the Princess Margaret Hospital were identified retrospectively in the leukemia database. Clinical data were obtained from the leukemia and transplant databases as well as from the clinical hospital records. A total of 131 patients were registered between January 1, 1995, and December 31, 2004. Cytogenetic data are available for 95 (72.5%) patients. These included 85 of 120 patients with AML/MDS (71%) and 10 of 11 patients with ALL (91%). Risks for AML/MDS were expressed as defined by Southwest Oncology Group (SWOG) criteria representing favorable, intermediate, and unfavorable risk as well as risk of unknown significance.25 Cytogenetic risks for patients with ALL were defined as previously published.26 Chromosomal changes with favorable prognosis included del(12p), t12p), high hyperdiploidy, t(10;14), t14q11-q13); intermediate prognosis was associated with normal karyotypes not in the favorable or unfavorable group, t(1;19), abn (9p), del (6q); unfavorable prognosis included t(9;22), t(4;11),−7,+8, abn(11q23), and low hypodiploidy.

Analyses were performed on the total cohort of patients and on subgroups of patients based on whether they received supportive care or intensive therapy. Intensive therapy was defined as induction treatment and/or transplantation. Patients were deemed eligible for a transplant if they were younger than 70 years old and survived 70 or more days after initiation of remission induction therapy. The 70-day time interval coincided with the shortest duration from induction therapy to transplant. Age-eligible patients with MDS proceeded directly to transplant.

Descriptive statistics such as the median, range, proportion, and frequency were used to summarize baseline characteristics. The Kaplan-Meier method was used to estimate OS from the date of diagnosis of leukemia/MDS. Estimates of follow-up were defined as the duration from date of diagnosis of leukemia to the last follow-up visit for patients who were known to be alive. Cox proportional hazards regression was used to identify potential predictors of survival univariately. An optimal multivariate model was constructed using forward stepwise selection, using all possible data (there were substantial missing white blood cell [WBC] and bone marrow blast data, which affects the sample size in the multivariate model). A Fisher exact test was used to test whether the cause of death was different between transplant and nontransplant patients, with cause of death defined as treatment-related versus all other causes. All tests were 2-sided and a P-value of .05 or less was considered statistically significant. The 95% confidence intervals (95% CI) were provided for statistics of interest.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

All 131 unselected, consecutive patients who presented with a second malignancy in the form of AML/MDS/ALL (98 AML, 22 MDS, 11 ALL) posttherapy for PST were evaluated. The median age at the time of diagnosis of their leukemia/MDS was 64.6 years (range, 18.0–92.2). Sixty-eight (52%) were female. The predominant PST included carcinomas of the breast (29.8%), prostate (16.8%), colon (9.2%), and gynecological cancers (8.4%). Baseline demographics are shown in Table 1. The time interval from diagnosis of PST to the development of AML/MDS/ALL was similar for patients who had received chemotherapy and/or radiation (median, 4.2 years) or were treated solely with surgery (median, 5.0 years) (P = .56). Cytogenetic data were available for 84% of patients who received only surgical treatment for their PST. The group of patients managed with chemotherapy and/or radiation had data for 75%. Both groups of patients showed a similar cytogenetic risk profile (P = .52) (Table 2). The risk profile was also similar for patients with unknown therapy for their PST. The distribution of patients with AML/MDS by cytogenetic risk group was 16.7% favorable, 50% intermediate, and 33.3%. unfavorable. None of the patients with ALL fell into the favorable risk category, 30% were intermediate, and 70% unfavorable risk.

Table 1. Baseline Characteristics of All Patients and Subgroups
CharacteristicsTotal cohortSupportive therapyIntensive therapy*TransplantNo transplant
No. (%)No. (%)No. (%)No. (%)No. (%)
  • AML indicates acute myeloid leukemia; ALL, acute lymphoblastic leukemia, MDS, myelodysplasia, WBC, white blood cell count; NA, not available.

  • *

    Including 5 patients with MDS proceeding directly to transplant.

  • Patients aged <70 years, surviving >70 days after start of induction therapy or immediate transplant.

No. of patients13151802428
Age
 Median [range]64.6 [18.0–92.2]72.4 [30.6–92.2]61.5 [18.0–81.8]41.6 [18.0–64.2]61.6 [26.1–69.9]
Years, primary to secondary
 Median [range]4.1 [0.0–56.7]4.0 [0.0–56.7]4.3 [0.0–42.7]3.5 [1.5–24.7]3.9 [0.1–33.1]
Gender
 Male63 (48.1)33 (62.8)31 (38.8)5 (20.8)11 (39.3)
 Female68 (51.9)19 (37.2)49 (61.2)19 (79.2)17 (60.7)
Diagnosis
 AML98 (74.8)33 (64.7)65 (81.3)17 (70.8)23 (82.1)
 ALL11 (8.4)2 (3.9)9 (11.2)2 (8.3)4 (14.3)
 MDS22 (16.8)16 (31.4)6 (7.5)5 (20.8)1 (3.6)
WBC, n=106
 Median [range]5.4 [0.05–193.0]5.3 [1.0–193.0]5.4 [0.05–183.6]7.4 [0.7–49.3]4.6 [0.6–163.0]
Blasts, n=51
 Median [range]0.80 [0.15–0.99]0.80 [0.15–0.99]0.73 [0.30–0.90]0.65 [0.15–0.95]
Cytogenetic risk
 Favorable14 (10.7)2 (3.9)12 (15.0)2 (8.3)5 (17.9)
 Intermediate38 (29.0)13 (25.5)25 (31.3)4 (16.7)10 (35.7)
 Unfavorable43 (32.8)17 (33.3)26 (33.5)9 (37.5)8 (28.6)
 Unknown8 (6.1)0 (0.0)8 (10.0)3 (12.5)3 (10.7)
 NA28 (21.3)19 (37.3)9 (11.2)6 (25.0)2 (7.1)
Primary site
 Breast39 (29.8)13 (25.5)26 (32.5)10 (41.7)11 (39.3)
 Prostate22 (16.8)15 (29.4)7 (8.8)0 (0.0)3 (10.7)
 Colon12 (9.2)7 (13.7)5 (6.2)0 (0.0)1 (3.6)
 Gynecologic11 (8.4)1 (2.0)10 (12.5)1 (4.2)2 (7.1)
 Bladder7 (5.3)2 (3.9)5 (6.2)0 (0.0)2 (7.1)
 Thyroid7 (5.3)1 (2.0)6 (7.5)4 (16.7)1 (3.6)
 Melanoma5 (3.8)2 (3.9)3 (3.8)2 (8.3)0 (0.0)
 Other27 (21.4)10 (19.6)18 (22.5)7 (29.2)8 (28.6)
Table 2. Impact of the Primary Solid Tumor Management by Surgery Compared With Chemotherapy and/or Radiation Including Strategies on Timing and Cytogenetic Phenotype of Emerging Acute Leukemias/MDS
 Therapy for PST unknownSurgery*Chemotherapy and/or radiation
No. (%)No. (%)No. (%)
  • PST indicates primary solid tumor.

  • *

    These patients did not receive chemotherapy and/or radiation.

  • The treatment of the primary solid tumor may have included surgery.

No. of patients343859
Median [range], y, time from primary to leukemia3.6 [0.2–28.5]5.0 [0.0–56.7]4.2 [0.0–42.7]
P.56 
Patients with known cytogenetic risk18 (60)32 (84)45 (75)
Favorable3 (16.7)3 (9.4)8 (17.8)
Intermediate9 (50.0)14 (43.7)15 (33.3)
Unfavorable6 (33.3)15 (47.9)22 (48.9)
P.52 
Intensive15 (44.1)24 (63.2)41 (69.5)
Supportive only19 (55.9)14 (36.8)18 (30.5)
P.659 

Overall Survival

Survival statistics for all 131 patients combined and for subgroups are listed in Table 3 and depicted in Figure 1A–D. The median (95% CI) survival of all patients independent of their therapy was 10.5 (95% CI: 8.7–13.2) months with a 2- and 5-year survival (95% CI) of 24.1% (17.7%–33.0%) and 15.6% (10.0%–24.3%) (Fig. 1A).

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Figure 1. Overall survival of patients from diagnosis of their acute leukemia/myelodysplasia (MDS). (A) Data for all 131 patients who were enrolled in the study. (B) Survival of patients treated intensively for their leukemia/MDS in comparison to patients managed with supportive measures. A significant difference was observed. (C) Survival data for patients treated for their primary tumor either surgically without chemotherapy and/or radiation and patients who had received chemotherapy and/or radiation. (D) Survival of transplant-eligible patients who received or did not receive an allograft. The data did not differ significantly.

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Table 3. Survival Statistics
Parameter (95% CI)Total cohortSupportive therapyIntensive therapy*TransplantNo transplantFavorable riskIntermediate riskUnfavorable risk
  • LFU indicates last follow-up.

  • *

    Including 6 patients with MDS proceeding directly to transplant.

  • Patients ages < 70 years, surviving > 70 days after start of induction therapy or immediate transplant.

No.13151802428143843
No. (%) Alive at LFU24 (18.3)1 (2.0)23 (28.8)9 (37.5)10 (35.7)5 (35.7)9 (23.7)7 (16.3)
Median [range] Follow-up, mo46.0 [7.8–110.5]89.9 [–]45.8 [7.8–110.5]63.2 [13.1–110.5]39.9 [11.7–77.7]71.3 [7.8–110.5]48.0 [11.7–89.9]39.7 [13.1–64.3]
Median survival. mo10.5 [8.7–13.2]6.5 [3.7–10.6]13.6 [10.2–17.6]17.6 [13.6–NR]16.1 [12.0–NR]13.7 [9.1–NR]10.3 [6.1–19.1]6.5 [2.9–13.3]
2-Year survival24.1 [17.7–33.0]7.8 [3.1–20.1]35.2 [25.8–47.8]48.7 [32.0–74.0]39.7 [24.6–64.0]44.9 [24.0–83.9]24.6 [13.9–43.7]21.5 [11.9–38.8]
3-Year survival20.2 [14.2–28.9]7.8 [3.1–20.1]28.4 [19.5–41.2]37.9 [12.9–62.3]34.0 [19.3–59.9]35.9 [16.7–77.0]24.6 [13.9–43.7]18.4 [9.5–35.8]
5-Year survival15.6 [10.0–24.3]2.0 [0.3–13.7]26.6 [17.9–41.2]37.9 [12.9–62.3]34.0 [19.3–59.9]35.9 [16.7–77.0]21.1 [11.0–40.4]13.8 [5.8–33.1]
P<.001 .59 .055  

Seventy-five patients (57.3%) underwent induction therapy, 5 patients (3.8%) with MDS proceeded immediately to transplant, and 51 (38.9%) were managed with supportive care. The 80 patients managed intensively had a median (95% CI) survival of 13.6 (10.2–17.6) months and the 2- and 5-year survival (95% CI) was estimated to be 35.2% (25.8%–47.8%) and 26.6% (17.9%–41.2%). Twenty-three (28.8%) were alive at last known follow-up.

The subgroup of 51 patients managed solely with supportive measures because of prohibitive comorbidity or patient preference had a median survival (95% CI) of 6.5 (3.7–10.6) months with a 2- and 5-year survival (95% CI) of 7.8% (3.1%–20.1%) and 2.0% (0.3%–13.7%). Only 1 patient remains alive 89.9 months after diagnosis of intermediate risk MDS secondary to prostate cancer. The difference in median survival (13.6 vs 6.3 months) favoring patients treated with induction therapy or by immediate transplant was statistically significant (P < .001, hazard ratio [HR] for supportive measures 2.13 [1.45–3.13], Fig. 1B).

Patients receiving intensive therapy tended to be younger (median age, 61.5 vs 72.4), more likely to be female (61.2% vs 37.2%), and suffering from AML (81.3% vs 64.7%) compared with patients who received supportive therapy (Table 1). The impact of age as a potential confounding variable was evaluated by comparing the outcome of patients below and above the median (65 years) managed intensively or by supportive care (Table 4). Patients of the younger age group treated intensively had a superior outcome compared with patients sustained with supportive measures (P ≤ .001, HR for supportive measures 2.98 [1.64–5.47]). The survival difference between patients receiving intensive or supportive therapy was not significant for the older age group (P = .32, HR for supportive measures 1.31 [0.77–3.13]).

Table 4. Subpopulation Survival Analysis
 No.PHazards ratio (95% CI)
Supportive vs intensive
 Total cohort131<.0012.13 (1.45–3.13)
 Age <6567<.0012.98 (1.64–5.42)
 Age ≥6564.321.31 (0.77–2.23)
Transplant vs no-transplant
 Eligible cohort52.590.83 (0.42–1.65)
 Age <5624.6651.33 (0.37–4.76)
 Age ≥5628.420.63 (0.21–1.9)
Surgery vs chemo/radiation
 Cohort with known PST therapy97.80.94 (0.59–1.5)
 Intensive65.320.73 (0.4–1.35)
 Supportive only32.0332.56 (1.08–6.06)

Of transplant-eligible patients, those who received transplants were younger (median age 41.6 vs 61.6), more likely to be female (79.2% vs 60.7%), with a higher WBC (median WBC 7.4 vs 4.6), and were more likely to present with unfavorable cytogenetic risk (9 of 15 = 60% vs 8 of 23 = 35% of those with known cytogenetic risk) (Table 1). The impact of age on OS in this generally younger group of patients who were either transplanted or not was examined by comparing the survival of patients below and above the median age (56 years). An age-related difference in survival between transplanted and not transplanted patients was not observed (P = .665, HR 1.33 [0.37–4.76] for ages < 56 years, P = .42, HR 0.63 [0.21–1.9] for ages ≥56 years) (Table 4).

The survival of patients who had developed leukemia/MDS after surgery did not differ from that observed for patients treated with chemotherapy and/or radiation (P = .8; Fig. 1C). In the surgical Group 24 patients were treated intensively, 14 with supportive care. In the group of patients managed with chemotherapy/radiation 41 received intensive treatment and 18 supportive care. These distributions did not differ significantly (P = .659, Table 2). The survival for patients in both groups was not significantly different for the patients who were exposed to intensive treatment (P = .32, HR = 0.73 [0.4, 1.35]) but they were different for those who were exposed to supportive treatment (P = .33, HR = 2.56 [1.08, 6.06]), indicating a higher hazard for the surgical group (Table 4).

Survival of Allografted Patients

A subset of 52 patients was deemed eligible for allogeneic transplants based on their age and disease status. Twenty-four of these patients had a donor (19 related and 5 unrelated) and all proceeded to transplant. Twenty of the transplants were performed with myeloablative and 4 with nonmyeloablative regimens. The 28 patients without a donor did not receive a transplant.

The survival was similar regardless of whether patients received or did not receive the transplant. Nine transplanted patients (37.5%) were still alive at last follow-up, with a median survival of 17.6 months and a 5-year survival of 37.9%. In comparison, 10 of the nontransplanted patients (35.7%) were alive at last follow-up with a median survival of 16.1 months and a 5-year survival of 34% (Fig. 1D). Although the survival curve for transplanted patients was almost entirely superior to the curve for nontransplanted patients, this difference was not statistically significant (P = .59). Similar results were observed for the subset of breast cancer patients, who represented the largest single disease category (P = .79) (data not shown). There was no difference in the number of deaths (P = .78) or the estimated survival (P = .51) between patients with or without a transplant. However, the causes of death were different (P < .001). Patients who underwent a transplant experienced more treatment-related deaths (11 of 15 = 73% vs 2 of 18 = 11.1%) and fewer deaths related to recurrence (2 of 15 = 13.3% vs 12 of 18 = 66.7%). These data are summarized in Table 5. Treatment-related mortality (TRM) among transplant recipients included chronic graft-versus-host disease (GVHD) (2), multiorgan failure (MOF) (2), renal failure (2), septic shock and renal failure (2), hemorrhage (1), interstitial pneumonitis/disseminated intravascular coagulation (DIC) (1), and venoocclusive disease (VOD)/pulmonary hemorrhage (1). TRM in patients not receiving a transplant included sepsis due to Candida (1) and Enterococcus faecalis (1).

Table 5. Causes of Death
 TransplantNo transplantP
  • *

    Test of transplant-related mortality versus all other causes of death.

  • Test of relapse mortality versus all other causes of death.

No. of patients2428
Causes of deathNo. (%)No. (%) 
 Treatment-related11 (73.3)2 (11.1)<.001*
 Relapse2 (13.3)12 (66.7).004
 Primary-related1 (6.7)2 (11.1)
 Other1 (6.7)2 (11.1)

Parameters Influencing Survival

Several clinical parameters were evaluated to examine their impact on OS. These included age, sex, primary tumor type, therapy of the primary malignancy, WBC, bone marrow blasts, cytogenetic phenotype, and time from diagnosis of primary malignancy to development of leukemia. Univariate and multivariate predictors of OS are shown in Table 6. Patients with unavailable cytogenetic data and patients with cytogenetic abnormalities of unknown significance were excluded from the analysis.

Table 6. Univariate and Multivariate Cox Proportional Hazards Regression Predictors of Overall Survival
ParameterHazards ratio (95% CI)P
  1. *N = 131 when not indicated otherwise.

Age (/10 y)1.23 (1.08–1.40).001
Male1.33 (0.91–1.94).145
Primary .086
 Breast0.79 (0.45–1.38) 
 Prostate1.14 (0.62–2.12) 
 Colorectal1.96 (0.94–4.06) 
 Gynaecological2.02 (0.97–4.18) 
 Bladder1.16 (0.47–2.87) 
 Thyroid0.51 (0.18–1.48) 
 Melanoma0.93 (0.35–2.47 
White blood cells, n = 1061.10 (1.05–1.16)<.001
Bone marrow blasts, n = 510.94 (0.24–3.63).93
Cytogenetic risk, n = 951.38 (0.99–1.92).060
Primary diagnosis to leukemia, y1.12 (0.85–1.48).42
Multivariate model, n = 78  
Age, /10 y1.27 (1.05–1.53).014
Cytogenetic risk1.69 (1.12–2.53).011
White blood cells1.10 (1.03–1.17).003

Results of the univariate Cox proportional hazards regression are presented in Table 6. Age and number of white blood cells (P = .001 and < .001, respectively) were the only statistically significant predictors of survival, although cytogenetic risk (P = .06) trended toward statistical significance. Increased age (HR = 1.23, 95% CI: = 1.08–1.40), increased number of white blood cells (HR = 1.10, 95% CI: 1.05–1.16), increased cytogenetic risk (HR = 1.38, 95% CI: 0.99–1.92), and male sex (HR = 1.33, 95% CI: 0.91–1.94) were predictive of poorer survival. Primary tumor therapy and time interval between the primary tumor and development of leukemia/MDS did not influence outcome. Multivariately, increased age (HR = 1.27, 95% CI: = 1.05–1.53, P = .014), increased cytogenetic risk (HR = 1.69, 95% CI: = 1.12–2.53, P = .011), and increased white blood cell counts (HR = 1.10, 95% CI: = 1.03–1.17, P = .003) all were predictive of shorter survival. Because of missing data, this analysis used data from only 78 total patients. The potential contribution by missing data for the remaining 53 patients not included in the model was examined either by t- or chi-squared test depending on the type of variable. The OS of patients with missing data was similar to that observed for the patients who contributed to the multivariate model (P = .95).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A study is presented that examined risk factors, the therapeutic approach, and treatment outcome of patients with leukemia/MDS after the management of a PST. One of the objectives was to determine the impact of the primary tumors and their management on the timing and association with cytogenetic risk factors in emerging leukemias/MDS. A second objective was to evaluate the role of intensive induction therapy and consolidation with allografting in comparison to conservative therapy or supportive measures. The study was performed on a cohort of 131 unselected patients who presented consecutively for management to a single center. The cohort was heterogeneous with respect to the PST and their therapy, presentation, and characteristic features of treatment-related leukemia/MDS performance status and age. Consistent with previous reports,16, 17 OS of the whole cohort was poor, with a median survival of 10.5 months and a 5-year survival of 15.6%. Differences in age and WBC as well as cytogenetic risk contributed to survival as determined by univariate and multivariate analysis. This has been well documented by previous studies. It is of note that 1 of the published series of patients with treatment-related AML/MDS, although showing the expected outcome differences related to cytogenetic risk, demonstrated inferior survival of each category when compared with respective controls of patients with de novo AML.17

As a novel observation, OS of our current study was not influenced by the nature and treatment of the primary malignancy. It is of note that we were unable to detect any significant time difference from the primary malignancy to the development of leukemia/MDS regardless of whether patients were treated with surgery alone or management strategies that included the use of chemotherapy and/or radiation. It should also be mentioned that the cytogenetic risk group distribution was similar for patients treated with chemotherapy and/or radiation and patients who underwent surgery alone, and that the survival of patients who developed leukemia in both groups did not differ. This novel observation raises the question of which contributions to leukemogenesis are attributable to preexisting genetic instability that may have resulted in the development of the primary tumor compared with the administration of cytotoxic drugs and radiation. This intriguing observation needs to be confirmed in a larger study. A significant survival difference was observed favoring patients who were medically able and willing to undergo intensive therapy compared with patients managed solely with supportive measures. By and large, patients undergoing intensive therapy were younger and presented generally with a better performance status. We asked the question whether or not the difference in survival is a consequence of intensive versus supportive therapy or can be explained by differences in age alone. The difference in survival maintained its significance for patients younger than 65 years old who were treated with either intensive or supportive therapy. The difference was not seen for older patients. On the basis of this observation it appears to be reasonable to offer intensive therapy to younger patients presenting with acceptable comorbidities.

Further intensification of disease management by allografting did not improve survival despite a significantly lower recurrence rate. The latter observation is consistent with a superior antileukemic effect of allografts in the management of these high-risk patients. Unfortunately, the benefit of better disease control was offset by increased treatment-related mortality. The data are in keeping with previous reports.15, 23 The high transplant-related mortality is not surprising given the finding that the majority of these generally heavily pretreated patients were transplanted after administration of a myeloablative regimen. The number of nonmyeloablative transplants in this series is too small to determine whether or not the use of preparative regimens of reduced intensity may result in a more favorable outcome. This strategy deserves further evaluation and the feasibility was recently demonstrated in a study involving 26 patients.27

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Curtis RE,Boice JDJr,Stovall M, et al. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med. 1992; 326: 17451751.
  • 2
    Fisher B,Rockette H,Fisher ER,Wickerham DL,Redmond C,Brown A. Leukemia in breast cancer patients after adjuvant chemotherapy or postoperative radiation: the NSABP experience. J Clin Oncol. 1985; 3: 16401658.
  • 3
    Fisher B,Anderson S,Wickerham DL, et al. Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol. 1997; 15: 18581869.
  • 4
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