Secondary lymphoblastic leukemia has been rarely reported in patients with multiple myeloma.
We report 3 cases of secondary lymphoblastic leukemia in multiple myeloma patients. They shared a similar phenotype of myeloma cells and secondary lymphoblasts. The chemotherapy treatments in the 3 patients were complex due to various factors.
Multiple immune defects caused by exposure to a variety of agents can play an important role in the development of secondary lymphoblastic leukemia. Microscopic morphology and flow cytometry are important means to detect secondary malignancies in multiple myeloma. Further clinical, experimental and genetic studies of secondary malignancies in multiple myeloma will be necessary in the future.
Tumori 2016; 102(Suppl. 2): e131 - e136
Article Type: CASE REPORT
AuthorsLi Junxun, Liu Junru, Chen Meilan, Liang Chujia, Chen Shaoqian, Zhan Jieyu, Ye Zhuangjian, Zhang Fan, Ouyang Juan, Cheng Jing, Li Juan
- • Accepted on 25/05/2015
- • Available online on 02/07/2015
- • Published online on 11/11/2016
This article is available as full text PDF.
Multiple myeloma (MM) is a malignant plasma cell neoplasm characterized by plasma cells accumulating in the bone marrow, with subsequent destruction of bone, symptoms of bone marrow failure, and organ dysfunction (1, 2). Recent studies have shown that acute myeloid leukemia (AML) and myelodysplasia (MDS) may represent secondary hematological malignancies of MM (3-4-5-6); however, cases of secondary lymphoblastic leukemia in MM have rarely been reported (3-4-5-6). In this article, we report 3 cases of secondary lymphoblastic leukemia occurring after complex therapy with bortezomib, dexamethasone, thalidomide and anthracyclines. We then provide a brief review of the literature.
Case reports (
Characteristics and treatment of patients in the present study and in the literature
|Case||1||2||3||Lau (7)||Ueda (8)||Piszcz (9)|
|MM = multiple myeloma; VDJ = variable - diversity - junctional; ASCT = autologous stem cell transplant; CR = complete remission; nCR = near-complete remission; NR = non remission; PR = partial response; MLL = mixed lineage leukemia gene rearrangement; VADM = vincristine, pirarubicin, dexamethasone, melphalan; PAD = bortezomib, dexamethasone, doxorubicin; DVD = doxorubicin, vincristine, dexamethasone; VAD = vincristine, doxorubicin, dexamethasone; VCMP = vincristine, cyclophosphamide, melphalan, prednisone; VD = bortezomib, dexamethasone; VTD = bortezomib, dexamethasone, thalidomide; MPT = melphalan, prednisolone, thalidomide.|
|VADM regimen: vincristine 0.5 mg from day 1 to day 4; pirarubicin 10 mg from day 1 to day 4; dexamethasone 20 mg from day 1 to day 4; melphalan 12 mg from day 1 to day 4|
|VD regimen: bortezomib 2.0 mg on days 1, 4, 7 and 11, dexamethasone 20 mg/day on days 1, 2, 4, 5, 7, 8, 11 and 12|
|PAD regimen: bortezomib 2.5 mg days 1, 4, 8 and 11, dexamethasone 10 mg days 1-4, doxorubicin hydrochloride 60 mg day 4|
|VTD regimen: bortezomib 2.5 mg days 1, 4, 8 and 13; dexamethasone 20 mg days 1-4; thalidomide 200 mg/day|
|DVD regimen: doxorubicin 60 mg/day 1, vincristine 2 mg/day 1, dexamethasone 10 mg/days 1-4|
|VD regimen: bortezomib 1.9 mg days 1, 4, 8 and 11, dexamethasone 20 mg days 1-4|
|Age at MM diagnosis (years)||66||60||33||60||61||56|
|Immunoglobulin/level||IgG-κ/78 g/L||IgG-κ/97.1 g/L||IgG-λ/42.1 g/L||IgG-κ||IgD-λ||IgG|
|Plasma cell % in bone marrow||19%||67%||16.5%||50%||50%||11.2%|
|Hemocytopenia at primary MM||No||No||Anemia||Anemia||/||/|
|Induction therapy||VADM 2 cycles||PAD 4 cycles||DVD 1 cycle||VAD 4 cycles||High-dose dexamethasone 4 cycles||VCMP 7 cycles|
|Responsiveness to chemotherapy||CR||nCR||NR||CR||Very good PR||PR|
|Consolidation therapy||VD 2 cycles||VTD 1 cycle||VD 4 cycles||/||/||MPT 9 cycles|
|Radiation therapy||No||20 times||No||No||No||No|
|ASCT||No||4 months after diagnosis||4 months after diagnosis||6 months after diagnosis||7 months after diagnosis||No|
|Maintenance therapy||Lenalidomide/thalidomide||Thalidomide||Thalidomide||High-dose melphalan (140 mg/m2)||High-dose melphalan (200 mg/m2)||Thalidomide|
|CR duration||34 months||32 months||73 months||35 months||11 months (PR)||52 months (PR)|
|Age at lymphoblastic leukemia diagnosis (years)||65||63||39||63||62||65|
|Percentage of lymphoblasts||68%||84%||84%||90%||94%||37.8%|
In July 2009, a 65-year-old female Han Chinese patient was admitted to our hospital with bone pain as chief complaint. A metastatic bone survey (MBS) of the skeleton revealed multiple focal osteolytic lesions. Complete blood count was normal. Serum protein electrophoresis revealed the presence of a monoclonal protein in the gamma region, which was subsequently identified as IgG immunoglobulin and kappa light chain. Plasma cells accounted for 19% of the nucleated cells in the bone marrow (
The myeloma cells and lymphoblast in the patients’ bone marrow smears.
The patient was diagnosed with multiple myeloma (Durie-Salmon IIA) and received 2 cycles of the VADM regimen. Complete remission (CR) was achieved. Lenalidomide (10 mg/day) was used as maintenance therapy from September 11, 2009. However, due to financial constraints the patient refused further lenalidomide. She therefore received consolidation therapy with the VD regimen for 2 cycles from November 5, 2010. Thalidomide (200 mg/day) was used as maintenance therapy from February 1, 2010 to October 13, 2012.
The patient was readmitted to our hospital with serious dizziness of more than 10 days’ duration. This time, immunoelectrophoresis was normal. Lymphoblasts accounted for 68% of the nucleated cells in a bone marrow smear (
A 63-year-old male Han Chinese patient was admitted to our hospital in September 2010 with back pain as the chief complaint. With a medical history including hypertension and diabetes mellitus for 4 years, he was given Norvasc (5 mg/day), Levemir (20 IU QM) once monthly, NovoNorm (1 mg tid) and glucophage (0.5 g tid) as treatment. The results of flow cytometric analysis (CD38+, CD138+, CD19–, CD56+, CD54+, CD20–, CD49e–) were consistent with the presence of clonal plasma cells.
The patient was diagnosed with MM (Durie-Salmon IIIB) and given the PAD regimen for 4 cycles from December 2010 to March 2011. The patient achieved near-complete remission (nCR). With informed consent, the patient underwent autologous stem cell transplantation (ASCT) on May 13, 2011.
However, follow-up PET-CT showed a high SUV in some of the focal osteolytic bone lesions, even after 20 radiotherapy sessions (2 Gy per fraction, directed to the left fifth rib). The VTD regimen was therefore given as consolidation therapy from September 1, 2011. After 1 course of therapy the patient achieved CR. He was started on thalidomide (200 mg/day) as maintenance therapy in October 2011.
He was readmitted to our hospital in May 2014 with serious fatigue as the chief complaint. Immunoelectrophoresis showed no monoclonal band. The patient had a low platelet count (33 × 109/L).
Lymphoblasts accounted for 84% of nucleated cells in the patient’s bone marrow smear (
A 33-year-old female Han Chinese patient was admitted to our hospital in September 2006 with serious fatigue as chief complaint. MBS revealed multiple focal osteolytic bone lesions. Complete blood count showed a low hemoglobin level (51 g/L). Plasma cells accounted for 16.5% of the bone marrow cells (
The patient was diagnosed with MM (Durie-Salmon IIIB). The DVD regimen was given for 1 cycle from December 2006; however, the patient did not benefit much from the treatment. Therefore the VD regimen was given for 4 cycles from April 2007. The patient achieved nCR and underwent ASCT on April 29, 2007.
Thalidomide (200 mg/day) was used as maintenance therapy from January 2008. The dosage was reduced to 150 mg/day because of mild numbness and dizziness. In March 2013, the patient was diagnosed with hypertension and was therefore prescribed valsartan (80 mg/day) and amlodipine (5 mg/day). CR was maintained until April 2014, when the patient was readmitted to our hospital with serious cough as chief complaint. Immunoelectrophoresis showed no monoclonal band. The level of beta-2 microglobulin (2,180 μg/L) was elevated while the level of hemoglobin (109 g/L) was slightly low. Plasma cells accounted for 2% and lymphoblasts for 84% of the nucleated cells in the bone marrow smear (
All the records of these 3 patients were reviewed. Unexpectedly, a very low percentage (<0.005%) of blast cells was found in their bone marrow smears during maintenance therapy (
Blast cells found in the bone marrow smears during maintenance therapy. Case 1 (A), case 2 (B) and case 3 (C). The blast cells in Figure 2A, 2B and 2C are similar to the lymphoblasts described in Figure 1A, 1C and 1E, respectively.
IgH rearrangements in the MM phase were positive in case 1 and case 3, and negative in case 2. IgH rearrangement in the lymphoblastic leukemia phase was positive in cases 1 and 2 (
Fluorescence in situ hybridization results of the MM phase and ALL phase in the 3 cases. MM phase of case 1: positive (A); ALL phase of case 1: positive (B); MM phase of case 2: negative (C); ALL phase of case 2: positive (D); MM phase of case 3: positive (E). MM = multiple myeloma; ALL = acute lymphoblastic leukemia.
In recent years, new agents have prolonged the survival of MM patients, but a concerning finding is the increased incidence of secondary malignancies (3-4-5-6). Mailankody et al (3) calculated the standardized incidence rates for all subsequent hematological and nonhematological malignancies for more than 8,740 MM patients. Sixty-nine and 508 of the patients were diagnosed with a second hematological and nonhematological malignancy, respectively (3). To our knowledge, most secondary hematological malignancies were either AML or MDS. Secondary lymphoblastic leukemia in MM is rarely seen and has been reported in only 3 published papers (7-8-9). In the present article we reported 3 cases of secondary lymphoblastic leukemia in MM and we tried to find out if there were any common characteristics.
Noticeably, all 3 patients shared a similar treatment process: they received bortezomib, anthracycline and dexamethasone either as induction or consolidation therapy and thalidomide as maintenance therapy. Furthermore, they underwent regimen changes during the course of treatment (for economic reasons or because of limited therapy effect), increasing the chances of exposure to more chemotherapeutics (
By contrast, 3 special cases were found by reviewing the 3 papers on secondary ALL mentioned above (7-8-9). All 3 patients received dexamethasone and melphalan but no bortezomib; furthermore, no CD33 expression was present in the lymphoblasts (
Bortezomib, which is linked to decreased numbers of NK cells and CD8+ T cells and alteration of dendritic cell function (10), was a principal medicine in the treatment of the 3 patients described by us. However, according to San Miguel et al (11) there was no significant difference in the incidences of secondary malignancies between a VMP (bortezomib, melphalan and prednison) group and an MP (melphalan and prednisone) group. Bortezomib was associated with a relatively low incidence of secondary malignancies. Our patients had short exposure to bortezomib (less than 2 months) and therefore we speculate that bortezomib may not be the main cause of the secondary lymphoblastic leukemia in our patients.
The exposure time to thalidomide in these 3 patients was relatively long (it lasted 32-73 months as maintenance therapy). However, thalidomide was associated with a relatively low incidence of secondary malignancies compared with other immunomodulatory agents. Studies have found that thalidomide can have both immunostimulatory and immunosuppressive activity.
Usmani and colleagues (14) compared the incidence of secondary malignancies between a control group (no thalidomide) and an experimental group (thalidomide for induction, consolidation and maintenance therapy and transplantation). No significant difference was observed. Stewart et al (15) conducted a randomized phase III trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM. They found that 8 (4.8%) and 6 (3.7%) patients developed secondary malignancies in the thalidomide-prednisone group and observation group, respectively. Though the difference was not calculated, it seemed not significant (15). These studies would suggest that the use of thalidomide does not increase the risk of secondary malignancies.
Further research has shown that melphalan seems to elevate the risk of secondary malignancies. According to Schütt et al (16), conventional-dose chemotherapy (melphalan, cyclophosphamide) with or without steroids reduced the numbers of CD4+(T helper) cells, CD4+/CD45RO+ cells (memory T cells) and CD19+ cells (B-lineage cells). In addition, high-dose chemotherapy was shown to prolong the observed immunosuppression. This resulted in an increased incidence of opportunistic infections such as cytomegalovirus infection, pneumocystic pneumonia, and varicella-zoster virus infection. Opportunistic infections were correlated with severely reduced CD4+ T-cell, CD4+/CD45RO+ cell and CD19+ cell counts (16). Furthermore, chemotherapy was associated with direct DNA damage and genetic mutations, potentially adversely impacting the immune system (17).
Bergsagel et al (18) carried out a prospective study on secondary malignanies in MM. They found that the incidence of MDS or acute leukemia was associated with long-term use of 3 alkylating agents: melphalan, cyclophosphamide and carmustine. Similar results from a study by Cuzick et al (19) indicated that the accumulated dose of melphalan in 3 years might be the main risk factor for secondary malignancies in MM.
Our 3 patients had received anthracyclines in their induction therapy. However, the therapeutic effects were unsatisfactory. Although anthracyclines are known to have cardiotoxicity, few papers have reported on its relation to triggering secondary tumors. Secker-Walker et al (20) reported that 14 of 40 patients with mixed lineage leukemia gene rearrangement (MLL) abnormalities who developed secondary tumors had received anthracyclines. Sandoval et al (21) inferred that anthracyclines may cause secondary AML if combined with either alkylating agents or irradiation. Case 1 of the present study had received pirarubicin combined with melphalan while case 2 received doxorubicin and subsequent irradiation. Yet, they both developed secondary ALL, but not AML.
CD33 is an important myeloid antigen. In the past, it was believed that the prognosis of ALL showing expression of myeloid antigen (Mye(+)ALL) was poorer than that of ALL with no myeloid antigen expression (Mye(–)ALL). However, recent papers suggested that there was no significant difference between the prognosis of these 2 groups (22-23-25). As previously mentioned, our 3 cases were different from those described in other reports. Their lymphoblasts presented CD33 expression in varying degrees. Our hypothesis is that this might be highly related to the patients’ similar medication regimens: they received bortezomib, anthracycline and dexamethasone either in induction or consolidation therapy and thalidomide in maintenance therapy. As mentioned above, anthracyclines may cause secondary AML if combined with alkylating agents or irradiation (21). However, our patients developed Mye(+)ALL.
According to the available literature, it was difficult to distinguish whether the secondary lymphoblastic leukemia of our 3 patients was triggered by any single agent during their treatment or not. The treatments of these 3 patients were complex due to various reasons. The change of chemotherapy regimen may have led these patients to be exposed to more chemotherapeutic drugs. As a result of the exposure to various agents, it could be inferred that multiple immune defects may have played a role in the development of secondary lymphoblastic leukemia in these 3 patients.
A very low percentage of blast cells was found in the bone marrow smears of our 3 patients during maintenance therapy. Based on the morphology of the blast cells, we supposed the lymphoblasts might have existed during maintenance therapy before lymphoblastic leukemia occurred. Further flow cytometric analysis revealed that the 3 patients shared a lymphoblast phenotype that was positive for CD10, CD34, HLA-DR and CD33 (from diminished to positive). We speculate that microscopic morphology and flow cytometry can be important in the detection of secondary malignancies in MM. Once abnormal cells are detected in bone marrow smears, further flow cytometry analysis should be performed. If monoclonal lymphoblasts are present, especially with an abnormal immunophenotype such as CD33 expression, secondary lymphoblastic leukemia is highly likely.
Unfortunately we did not have enough specimens to run IgH rearrangement tests for all 3 patients in both the MM and ALL phase. We did find that IgH rearrangement was negative in the MM phase but positive in the ALL phase in case 2. This would suggest that 2 distinct monoclonal B-cell populations participate in the pathogenesis of these 2 lymphoid malignancies at the 2 time points. This is consistent with the 3 reports describing the occurrence of secondary lymphoblastic leukemia in MM (7-8-9).
In conclusion, we reported on 3 MM patients who developed secondary lymphoblastic leukemia after complex treatments with bortezomib, anthracycline, dexamethasone and thalidomide. Multiple immune defects caused by exposure to a variety of agents might have existed in these patients and played an important role in the development of secondary lymphoblastic leukemia. Microscopic morphology and flow cytometry are important to the detection of secondary malignancies in MM. Although the administration of new agents prolongs the survival time of MM patients, further clinical, experimental and genetic studies of secondary malignancies in MM are necessary.
Stewart AK Trudel S Bahlis NJ et al. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. 2013 121 9 1517 1523
Cuzick J Erskine S Edelman D Galton DA A comparison of the incidence of the myelodysplastic syndrome and acute myeloid leukaemia following melphalan and cyclophosphamide treatment for myelomatosis. A report to the Medical Research Council’s working party on leukaemia in adults. 1987 55 5 523 529
- Junxun, Li [PubMed] [Google Scholar] 1
- Junru, Liu [PubMed] [Google Scholar] 3
- Meilan, Chen [PubMed] [Google Scholar] 3
- Chujia, Liang [PubMed] [Google Scholar] 1
- Shaoqian, Chen [PubMed] [Google Scholar] 1
- Jieyu, Zhan [PubMed] [Google Scholar] 2
- Zhuangjian, Ye [PubMed] [Google Scholar] 1
- Fan, Zhang [PubMed] [Google Scholar] 1
- Juan, Ouyang [PubMed] [Google Scholar] 1
- Jing, Cheng [PubMed] [Google Scholar] 1
- Juan, Li [PubMed] [Google Scholar] 3, * Corresponding Author (Lijuan2011001@126.com)
Department of Laboratory Science, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China
Department of Pediatrics, First Hospital of Baiyun District, Guangzhou - China
Department of Hematology, First Affiliated Hospital of Sun Yatsen University, Guangzhou - China