Efficacy and safety of bortezomib in patients with plasma cell leukemia

Authors


Abstract

BACKGROUND.

The prognosis of patients with plasma cell leukemia (PCL), an aggressive variant of multiple myeloma (MM), is usually poor. Bortezomib is the first proteasome inhibitor approved for the treatment of advanced MM. Currently available information regarding the role of bortezomib in PCL is scanty and derives from anecdotal, single–case reports.

METHODS.

The authors conducted a retrospective survey of unselected Italian patients with primary or secondary PCL who were treated with bortezomib outside of clinical trials. Twelve evaluable patients were recorded who had received bortezomib for 1 to 6 cycles as either a single agent or variously combined with other drugs. Three patients were treated with bortezomib as frontline therapy, and 9 patients received bortezomib after 1 to 4 lines of chemotherapy, including autologous stem cell transplantation and thalidomide.

RESULTS.

According to the International uniform response criteria of the International Myeloma Working Group, 5 partial responses (defined as a reduction in M-protein of >50%), 4 very good partial responses (defined as a reduction of >90% in M-protein), and 2 complete responses (defined as negative immunofixation) were achieved, for a response rate of 92%. Responses did not appear to be influenced by previous treatments or by other clinical or biologic parameters, including chromosome 13 deletion or the combination of bortezomib with other drugs. The median progression-free and overall survivals after bortezomib were 8 months and 12 months, respectively. At the time of last follow–up, 8 patients were alive 6 to 21 months after treatment with bortezomib, 4 of whom were in very good partial or complete responses. Grade 3/4 hematologic or neurologic toxicities (graded according to the Common Terminology Criteria for Adverse Events [CTCAE; version 3]) were reported to occur in 9 patients and 1 patient, respectively, whereas 6 patients experienced possible or documented infections.

CONCLUSIONS.

Bortezomib appears to be an effective drug for PCL that could significantly improve the usually adverse clinical outcome of these patients. Cancer 2007. © 2007 American Cancer Society.

Plasma cell leukemia (PCL) is an aggressive, rare variant of multiple myeloma (MM) and is characterized by the presence of >20% and/or an absolute number of greater than 2 × 109/L plasma cells circulating in the peripheral blood.1, 2 PCL represents approximately 2% to 4% of all MM diagnoses and exists in 2 forms: primary PCL (approximately 60% of cases) presents ‘de novo’ in patients without previous evidence of MM, whereas secondary PCL (which accounts for the remaining 40% of cases) consists of a leukemic transformation occurring in approximately 1% of patients with a previously diagnosed MM.

The prognosis of PCL patients who are treated with standard chemotherapy is usually poor, with median survival being measured in months.3–11 Stem cell transplantation may be more effective in some but not all PCL patients.12–17

Bortezomib (Velcade) is the first proteasome inhibitor approved in the U.S. and European Union for the treatment of resistant/recurrent MM and is currently under investigation as a frontline chemotherapy approach.18–20 Some reports have suggested that bortezomib could be particularly effective in patients with extramedullary MM.21–24 However, to our knowledge, to date there are very few data regarding the efficacy of this drug in PCL.25–28

In the current study, we evaluated the therapeutic role of bortezomib in a retrospective, multicenter series of 12 patients with PCL who received this drug as either frontline therapy or during the course of their disease.

MATERIALS AND METHODS

We conducted a national retrospective survey of unselected patients with a diagnosis of PCL according to the International uniform response criteria of the International Myeloma Working Group who had received bortezomib for the treatment of their disease outside of clinical trials.29 Eight hematologic institutions participating in the Gruppo Italiano Studio Mieloma Multiplo (GISMM), Gruppo Italiano Studio Linfomi (GISL), and Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) cooperative groups enrolled at least 1 patient each. No PCL patient treated with bortezomib in these centers was excluded from the analysis.

Twelve patients who were diagnosed between October 2002, and August 2006 were evaluable (5 men and 7 women with a median age of 61.2 years [range, 42–74 years]). Informed consent was obtained to review the available clinical data in each case.

Table 1 summarizes the characteristics of the patients, 8 of whom had primary PCL and 4 of whom had secondary PCL. Nine patients had previously received 1 to 4 lines of chemotherapy before treatment with bortezomib, including autologous stem cell transplantation in 5 cases and thalidomide in 5 cases. Three patients received bortezomib as frontline therapy.

Table 1. Bortezomib in PCL: Clinical and Laboratory Characteristics of Treated Patients
Sex/Age, yPrevious treatmentsPrimary/SecondaryM-ProteinPeripheral blood plasma cells (%)White blood cells (× 109L)Hemoglobin (g/dL)Platelets (× 109L)Extramedullary diseaseKaryotype
  • PCL indicates plasma cell leukemia; M, male; VAD, vincristine, doxorubicin, and dexamethasone; Thal, thalidomide; ASCT, autologous stem cell transplantation; Ig, immunoglobulin; F, female; Del 13, chromosome 13 deletion; ND, not done; Mel, melphalan given intravenously; Dex, dexamethasone; MPTV, melphalan, prednisone, thalidomide, and bortezomib; MPT, melphalan, prednisone, and thalidomide; M-Dex, melphalan and dexamethasone; CVP: cyclophosphanide, vincristine, and prednisone.

  • *

    Abnormal creatinine level.

M/61VAD/Thal/ASCTPrimaryIgG kappa5012.710.470NoNormal
F/70NonePrimaryIgG lambda48817.125NoDel 13
F/65VAD/ASCTSecondaryIgG kappa5110.26.965JawDel 13
M/62*VAD/ASCTPrimaryKappa631137.558NoND
F/55VADPrimaryIgA lambda22129.436LiverND
M/61*NonePrimaryLambda37198.8140NoNormal
F/55VAD/ASCT/Mel/Thal-Dex/MPTVPrimaryKappa308.112.9202MuscleDel 13
F/66MPTSecondaryIgG kappa5312.98.773NoDel 13
M/74*Thal/M-Dex/VAD/CVPSecondaryIgA kappa238.98.430NoND
M/51VADPrimaryIgG kappa506.711.6209NoNormal
F/73NonePrimaryNon-secretory843411.2181Pleural effusionND
F/42VAD/ASCT/Thal-DexSecondaryIgG kappa1002780NoND

Circulating plasma cells ranged from 2 × 109/L to 71 × 109/L. Three patients had varying degrees of renal failure (serum creatinine levels of 1.55 mg/dL, 2.6 mg/dL, and 6.1 mg/dL, respectively), and 4 patients had extramedullary disease. A chromosome 13 deletion was observed in 4 of 7 patients with an available karyotype.

In all but 1 patient, bortezomib was given using the standard schedule of 1.3 mg/m2 on Days 1, 4, 8, and 11, with an interval of 10 to 12 days between 2 cycles. One patient was treated with a higher dose (1.5 mg/m2) of bortezomib. Four patients received bortezomib as single agent, and 8 patients received it in combination with other drugs (Table 2). A median of 4 cycles was administered (range, 1–6 cycles).

Table 2. Bortezomib in PCL: Characteristics of Treatments, Responses, Clinical Outcomes, and Toxicities
Associated drugsNo. of cyclesResponse*PFS, MonthsOS, MonthsHematologic toxicityNeurologic toxicityInfectious toxicityOther toxicities
  • PCL indicates plasma cell leukemia; PFS, progression-free survival; OS, overall survival; VGPR, very good partial response; Thal-Dex, thalidomide given at a dose of 100–200 mg/day and dexamethasone given at a dose of 40 mg/day for 4 days every 4 weeks; PR, partial response; PD, progressive disease; CR, complete reponse; Doxo-Dex, doxorubicin given at a dose of 40 mg m2 every 4 weeks and dexamethasone given at a dose of 40 mg/day for 4 days; ASCT, autologous stem cell transplantation; Thal, thalidomide; NA, not applicable.

  • *

    Responses were evaluated according to the International uniform response criteria of the International Myeloma Working Group (excluding progressive disease), and toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE; version 3).

  • Maintenance therapy with bortezomib, thalidomide, and dexamethasone.

  • Dose reduction required.

  • §

    Bortezomib was given at a dose of 1.5 mg/m2.

No6VGPR812Grade 4Grade 1NoRash, nausea, diarrhea (grade 1/2)
Thal-Dex6VGPR+7VGPR at +7Grade 4Grade 1Grade 3No
Thal-Dex6PR7PD at +8Grade 3Grade 1Grade 3No
No6CR+12CR at +12Grade 3Grade 3Grade 2No
No6PR5PD at +10Grade 2NoNoNo
Doxo-Dex4 (followed by ASCT)PR+7PR at +7Grade 3NoGrade 3No
Doxo-Dex4CR+21CR at +21Grade 2Grade 2NoNausea (grade 2)
Doxo-Dex2 (followed by ASCT)PR910Grade 4NoGrade 3Diarrhea (grade 2)
Thal5VGPR69Grade 4NoGrade 2Diarrhea (grade 1)
Doxo-Dex2 (followed by ASCT)VGPR+9VGPR at +9Grade 3NoNoNo
Doxo-Dex4§PR5PD at +6Grade 1NoNoNo
No1PDNA3Grade 4NoNoNo

Responses were graded according to the recently published International uniform response criteria30 as partial (PR) (defined as a reduction of >50% of M- protein and a reduction in the 24–hour urinary M-protein of >90% or to <200 mg per 24–hour period), very good partial (VGPR) (defined as serum and urine M-protein levels detectable by immunofixation but not on electrophoresis or a ≥90% reduction in the serum M-protein level plus the urine M-protein level of <100 mg per 24–hour period), and complete (CR) (defined as negative immunofixation on serum and urine, the disappearance of soft tissue plasmacytomas, and bone marrow plasma cells of <5%). Progression-free survival (PFS) and overall survival (OS) were evaluated beginning with the first month of treatment with bortezomib.

RESULTS

Table 2 summarizes the results. Overall, there were 5 PRs, 4 VGPRs, and 2 CRs, for a response rate of 92%. Plasma cells disappeared from the peripheral blood in 10 patients. Serum creatinine levels improved or returned to normal values in all patients who had abnormal renal function noted at baseline.

Responses did not appear to be influenced by the type or number of previous treatments or by other clinical or biologic parameters, including chromosome 13 deletion or the use of bortezomib as single agent or in combination with other drugs. However, it was interesting to note that the longest response was achieved in a patient who had previously been treated with a combination of bortezomib, melphalan, prednisone, and thalidomide and who again received bortezomib in association with doxorubicin and dexamethasone. In 3 patients, autologous stem cell transplantation procedures could be initiated after the response was achieved.

Overall, the median PFS and OS were 8 months and 12 months, respectively (Fig. 1A). The median PFS and OS in patients with primary PCL had still not been reached at 21 months (Fig. 1B). At the time of last follow–up, 8 patients were alive 6 to 21 months after therapy with bortezomib (4 of whom either in VGPR or CR) whereas 4 patients (including the only nonresponder) had died of progressive disease after 3 to 12 months.

Figure 1.

Progression-free survival (PFS) (blue lines) and overall survival (OS) (red lines) in (A) all patients with plasma cell leukemia (PCL) and (B) patients with primary PCL who were treated with bortezomib.

According to the Common Terminology Criteria for Adverse Events (CTCAE; version 3), grade 3/4 hematologic toxicity (mainly thrombocytopenia) occurred in 9 patients whereas reversible, grade 3 neuropathy was observed in only 1 patient (Table 2). Fever of unknown origin or documented infections (genitourinary tract, pneumonia, herpeszoster) were reported to occur in 6 patients. Other toxicities observed (diarrhea, nausea, skin rashes) never reached grade 3 (Table 2). In 3 patients, a reduction in the dose of bortezomib given was required due to hematologic or neurologic toxicity.

DISCUSSION

PCL is an aggressive variant of MM characterized by poor prognosis. The global response rate to standard chemotherapy in patients with primary PCL was reported to be 45% in 7 larger series including 136 patients.3, 4, 6–8, 10, 11 In these studies, the median OS was only 7 months (Table 3). In particular, conflicting data have been reported regarding the use of the combination of vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) or VAD-derived regimens.5, 6, 9, 10 In view of such disappointing results, autologous or allogeneic stem cell transplantation are currently recommended for eligible patients with primary PCL.2 Using these more intensive approaches, long–term survivals have been reported occasionally.12–15 Indeed, the median OS was reported to be approximately 36 months (range, 1–106 months) after autologous stem cell transplantation and approximately 20 months (range, 1–84 months) after allogeneic stem cell transplantation in 38 evaluable patients with primary PCL recently reviewed.16 However, even with these treatments, results may be unsatisfactory.17

Table 3. Response Rate and OS in Larger and More Recent Series of Patients With Primary PCL Who Were Initially Treated With Standard Chemotherapy (Single Alkylating Agents With or Without Steroids or Anthracycline-containing Regimens)
ReferenceNo. of patientsResponse rate, %Median OS, Months
  1. OS indicates overall survival; PCL, plasma cell leukemia.

Noel and Kyle, 1987325477
Bernasconi et al., 198948627
Dimopoulos et al., 19946273712
Garcia-Sanz et al., 1999726388
Costello et al., 2001818677
Vela-Ojeda et al., 20021024292
Jimenez-Zepeda and Dominguez, 2006118377
Total136457

Among new drugs for the treatment of MM, thalidomide has been reported to be temporarily effective in a small group of patients with PCL.31–33 To our knowledge, no data are currently available in the literature regarding the use of lenalidomide in this setting.

Secondary PCL often represents a terminal event for patients with advanced MM, which is usually nonresponsive to any treatment modality and demonstrates a median survival of only 1 to 2 months.1–4, 11

Bortezomib is a novel therapeutic agent with proven efficacy for the treatment of MM.18–20 It is interesting to note that some authors have suggested that bortezomib could be particularly useful for the treatment of MM patients with extramedullary disease.21–24 However, only sporadic, single–case reports have been published to date regarding the use of bortezomib in the setting of PCL. The efficacy of this drug, as a single agent or in sequence after other combination chemotherapies, has been reported both in primary PCL27 as well as in secondary PCL.26 Esparis-Ogando et al25 were the first to describe a heavily pretreated patient with secondary PCL, severe anemia, and thrombocytopenia in whom circulating plasma cells disappeared and peripheral blood counts returned to normal after treatment with bortezomib. Complete remission and successful stem cell mobilization also have been reported in patients with refractory PCL.28 However, this treatment needs to be carefully monitored because tumor lysis syndrome may occur in PCL patients receiving bortezomib.34

The results of the current study, which is the first performed in a relatively larger number of patients, indicate that bortezomib is effective in inducing significant responses in patients with primary or secondary PCL. Toxicity was found to be acceptable and some patients entered into high–quality remission phases, allowing to start intensive therapeutic programs after bortezomib. It is interesting to note that 4 of 5 patients who developed disease recurrence after autologous stem cell transplantation achieved a response, a finding that compares favorably with the results obtained with other salvage treatments for MM patients who undergo transplantation. We also emphasize that survival after bortezomib therapy was found to be longer than the entire OS previously reported for patients with primary PCL who receive standard chemotherapy (Table 3). This appears to be of particular significance if we consider that the majority of patients in the current study were not treated at the time of diagnosis and that some had developed disease recurrence after autologous stem cell transplantation or had secondary PCL, the prognosis of which is particularly poor. However, as expected, the best results were obtained in patients with primary PCL (Fig. 1B).

The reasons for a possible particular sensitivity of PCL to bortezomib remain speculative. Bortezomib reportedly reduces the in vitro growth of leukemic plasma cells more efficiently than dexamethasone or doxorubicin.25 Treatment with bortezomib also favors PCL cell apoptosis, inducing procaspase-3 and poly(ADP-ribose) polymerase cleavage and decreasing the amount of extracellular signal–regulated kinase (Erk1/2) and phospho-Erk1/2.25 The peculiar genetic and phenotypic characteristics of circulating and extramedullary neoplastic plasma cells35–37 could explain the sensitivity of these cells to bortezomib, but this remains to be formerly demonstrated.

In conclusion, the findings of the current study indicate that bortezomib is a useful agent for the treatment of patients with PCL, which could significantly improve the otherwise expected poor clinical outcome of these individuals. Therefore, we suggest that bortezomib be considered and investigated further (particularly in combination with other drugs and within transplantation programs) for the initial treatment of these patients.

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