Leukemia & Lymphoma, June 2015; 56(6): 1895–1896 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.974595
LETTER TO THE EDITOR
Lenalidomide as frontline therapy in polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes syndrome: a retrospective case series of eight patients
Leuk Lymphoma Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 08/31/15 For personal use only.
Elsa Lestang1,2,3, Aurelie Caristan1,3, Antoine Néel1,3, Julie Graveleau1, Elisabeth Duhamel4, Agathe Masseau1, Jerome Connault1, Hervè Maisonneuve5, Steven Le Gouill2,3, Nicolas Blin2, Cyrille Touzeau2, Philippe Moreau2,3 & Mohamed Hamidou1,3 1Service de médecine interne and 2Service d’hématologie, Centre Hospitalier Universitaire (CHU) Nantes, France, 3Faculté de Médecine, Université de Nantes, France, 4Service de médecine interne, Centre Hospitalier (CH) Saint Brieuc, France
and 5Service de médecine interne, Centre Hospitalier (CH) La Roche Sur Yon, France POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal [M] protein and skin changes) syndrome is a rare plasma cell disorder. The pathogenesis is mainly driven by pro-angiogenic (vascular endothelial growth factor [VEGF]) and pro-inflammatory (IL6) cytokines [1]. The name is an acronym derived from some of the main symptoms. Among them, neuropathy is one of the most disabling, for which conventional therapies provide only slow and moderate relief. Lenalidomide (Len), an immunomodulatory drug (IMID), has been suggested to be effective in this setting. We report on eight patients (not previously reported) with newly diagnosed POEMS syndrome treated with Len and dexamethasone (Len-Dex) in three departments of hematology and internal medicine in France between 2008 and 2013. The cohort consisted of three female and five male patients with a median age of 58 years (range 54–70 years). All patients met the Dispenzieri criteria for POEMS [2,3]. Three patients had localized disease, defined as having fewer than three bone lesions and no plasma cell infiltration detectable in the bone marrow biopsy. Five patients had systemic disease with at least three bone lesions plus bone marrow involvement. Clinically, all patients suffered from neuropathy involving the lower limbs. In three patients, impairment was severe, making them unable to walk, while in four patients, neuropathy was moderate, resulting in patients being able to walk with crutches. Six patients had skin changes (glomeruloid hemangioma, peripheral vascular disease, sclerotic lesions, facial erythrosis, lipoatrophy and hypertrichosis). Half of the patients had an extravascular fluid overload (localized in the lower limbs in two patients, and anasarca and polyserositis in two patients). Endocrine disorders were seen in 87.5% of cases (hypothyroidism in five patients and gynecomastia in two patients). Laboratory tests revelead that the M component was predominantly immunoglobulin A (IgA) with lambda restriction (6/8 patients). VEGF level measurements
were available in six patients and were found to be elevated in all cases. Morphological examinations by computer tomography (CT) and positron emission tomography-CT (PET-CT) detected osteosclerotic bone lesions in four patients mainly located in the iliac bone, vertebrae and costal bone. Castleman disease was diagnosed in one patient. All patients received Len-Dex, with Len administered at a dose of 25 mg per day on 21 consecutive days of a 28-day cycle and Dex administered at 40 mg weekly, together with a thromboembolism prophylaxis. Two patients with localized disease underwent radiotherapy on costal and thoracic vertebrae sites. The median number of cycles was 27.5 (range 4–51). Following two cycles of Len-Dex therapy, neurological impairment was assessed as stable in five patients, while marked improvement was documented in three patients who had severe impairment at diagnosis. Gynecomastia disappeared in two patients, and polyserositis and anasarca syndrome in two further patients. Fifty percent of patients were improved for hypertrichosis, facial erythrosis and glomeruloid hemangioma lesions. Hematological response was assessed according to International Myeloma Working Group (IMWG) criteria [4] and included complete response (CR), defined as negative immunofixation of the serum or normalization of the free light chain ratio, very good partial response (VGPR), as a 90% reduction in M protein, and partial response (PR), as a 50% reduction in M protein. After two cycles of Len-Dex, one patient achieved a CR, while six patients were in PR. Figure 1 represents the response obtained for each symptom in patients after the last cycle of Len-Dex or at the time of data collection (for patients still on therapy). Neurological response was seen in seven patients, with one CR in a patient with moderate symptoms at diagnosis and six in PR, while stabilization was achieved in one patient. Three patients reached CR for skin lesions and 75% of patients had a CR for
Correspondence: Professor Mohamed Hamidou, Internal Medecine Department, CHU Nantes, F-44093 Cedex 01, Nantes, France. Tel: ⫹ 33-2-40-08-31-46. Fax: ⫹ 33-2-40-08 33-79. E-mail: [email protected] Received 18 July 2014; revised 30 September 2014; accepted 5 October 2014
1895
1896 E. Lestang et al.
F G VE
om
po
ne
nt
as tia
O
lC
yn e M
on
oc lo
na
G
em
a
an
d
co m
VF
es ng ch a Sk in
Ed
Leuk Lymphoma Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 08/31/15 For personal use only.
N
eu
ro p
at hy
10 9 8 7 6 5 4 3 2 1 0
complete response
stable disease
partial response (+VGPR)
progression
Figure 1. Clinical and biological responses obtained after the last cycle of Len-Dex. VGPR, very good partial response (only for M component response); VFO, vascular fluid overload.
vascular fluid overload. For all patients, a response regarding the M component was observed, with 50% reaching CR and 50% PR. Serum VEGF levels decreased in all patients except for one who progressed, and this was associated with gynecomastia. The median follow-up was 26 months (range 5.1–65 months). At the time of the last follow-up, three patients were still receiving therapy, while the five remaining patients had stopped treatment due to four main reasons. One patient was scheduled for autologous stem cell transplant (ASCT) after four cycles of Len-Dex regardless of the response. Before ASCT, he achieved a neurological and hematological partial response. Another patient experienced progression of gynecomastia with an increase in VEGF level after 18 cycles of Len-Dex, while the free light chain ratio remained normal. In this case, VEGF was a predictive factor for relapse, as the VEGF level was found to start to increase several months prior to clinical relapse. The third patient experienced a grade 3 hematological toxicity necessitating treatment discontinuation. The two remaining patients no longer receiving therapy stopped treatment after obtaining good clinical and biological responses, and they did not experience relapse for between 5 and 15 months. The following toxicities were reported: one patient developed a venous thrombotic event despite prophylaxis, diarrhea occurred in 2 patients (grade ⬍ 3) and one patient had a localized skin rash (grade ⬍ 2). Reversible cytolytic hepatitis and cholestatic hepatitis were reported in one patient. Grade 3 anemia/thrombocytopenia occurred in a patient in hematological CR and neurological PR after six cycles. Treatment was stopped in this patient, resulting in a normalization of blood count with no sign of relapse. No aggravation of neuropathy or infections was observed. Our results resemble those reported by Zagouri et al. [5] who conducted a meta-analysis of Len-Dex studies in frontline and/or relapsed POEMS syndrome (n ⫽ 51 patients).
They reported that in 12 patients treated with frontline Len-Dex, the progression-free survival (PFS) at 12 and 24 months was 93% and 47.2%, respectively. In our series, the majority of patients had improvements in neurological symptoms following Len-Dex treatment, which is a major issue in this syndrome. This clinical effect of Len has previously been described [6], and in our experience it occurred fairly rapidly with a stabilization of symptoms after only two cycles, and the majority of patients achieved a PR. Similarly, we observed a rapid resolution of vascular fluid overload, multi-serositis and anasarca. IMIDs have both anti-angiogenic and immunomodulatory properties [7]. Thus in POEMS, Len might act on symptoms caused by the hypersecretion of VEGF as well as directly targeting the plasma cell clone, wich may explain the greater efficacy of Len over anti-VEGF treatment alone [8]. Nevertheless, there is a need to further investigate treatments for POEMS, as well as to define response criteria, duration of treatment and criteria to stop treatment. In young patients with systemic disease, high dose alkylating chemotherapy and ASCT is feasible and effective [9,10]. However, taking into account the balance of benefit, risk, quality of life, data from literature and our results, the question of delaying ASCT at the time of first relapse for young patients who have reached a good clinical response with smoldering-like disease status is of interest. A prospective, multicenter phase II trial is currently ongoing in France, and will further advance our knowledge regarding treatment strategies for this rare plasma cell disorder.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Kanai K , Sawai S, Sagawa K , et al. Markedly upregulated serum interleukin-12 as a novel biomarker in POEMS syndrome. Neurology 2012;79:575–582. [2] Dispenzieri A , Kyle RA , Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood 2003;101:2496–2506. [3] Dispenzieri A . POEMS syndrome. Hematology Am Soc Hematol Educ Program 2005:360–367. [4] Palumbo A , Sezer O, Kyle R, et al. International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia 2009;23:1716–1730. [5] Zagouri F, Kastritis E, Gavriatopoulou M, et al. Lenalidomide in patients with POEMS syndrome: a systematic review and pooled analysis. Leuk Lymphoma 2014;55:2018–2023. [6] Tomas JF, Giraldo P, Lecumberri R, et al. POEMS syndrome with severe neurological damage clinically recovered with lenalidomide. Haematologica 2012;97:320–322. [7] Shortt J, Hsu AK, Johnstone RW. Thalidomide-analogue biology: immunological, molecular and epigenetic targets in cancer therapy. Oncogene 2013;32:4191–4202. [8] Dietrich PY, Duchosal MA . Bevacizumab therapy before autologous stem-cell transplantation for POEMS syndrome. Ann Oncol 2008;19:595. [9] Dispenzieri A . Long-term outcomes after autologous stem cell transplantation in patients with POEMS syndrome. Clin Adv Hematol Oncol 2012;10:744–746. [10] Gronier S, Delmont E, Legros L, et al. [Efficacy of autologous peripheral blood stem cell transplantation (auto-PBSCT) on the neuropathic manifestations in POEMS syndrome]. Rev Neurol (Paris) 2014;170:37–45.
LETTER TO THE EDITOR
Lenalidomide as frontline therapy in polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes syndrome: a retrospective case series of eight patients
Leuk Lymphoma Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 08/31/15 For personal use only.
Elsa Lestang1,2,3, Aurelie Caristan1,3, Antoine Néel1,3, Julie Graveleau1, Elisabeth Duhamel4, Agathe Masseau1, Jerome Connault1, Hervè Maisonneuve5, Steven Le Gouill2,3, Nicolas Blin2, Cyrille Touzeau2, Philippe Moreau2,3 & Mohamed Hamidou1,3 1Service de médecine interne and 2Service d’hématologie, Centre Hospitalier Universitaire (CHU) Nantes, France, 3Faculté de Médecine, Université de Nantes, France, 4Service de médecine interne, Centre Hospitalier (CH) Saint Brieuc, France
and 5Service de médecine interne, Centre Hospitalier (CH) La Roche Sur Yon, France POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal [M] protein and skin changes) syndrome is a rare plasma cell disorder. The pathogenesis is mainly driven by pro-angiogenic (vascular endothelial growth factor [VEGF]) and pro-inflammatory (IL6) cytokines [1]. The name is an acronym derived from some of the main symptoms. Among them, neuropathy is one of the most disabling, for which conventional therapies provide only slow and moderate relief. Lenalidomide (Len), an immunomodulatory drug (IMID), has been suggested to be effective in this setting. We report on eight patients (not previously reported) with newly diagnosed POEMS syndrome treated with Len and dexamethasone (Len-Dex) in three departments of hematology and internal medicine in France between 2008 and 2013. The cohort consisted of three female and five male patients with a median age of 58 years (range 54–70 years). All patients met the Dispenzieri criteria for POEMS [2,3]. Three patients had localized disease, defined as having fewer than three bone lesions and no plasma cell infiltration detectable in the bone marrow biopsy. Five patients had systemic disease with at least three bone lesions plus bone marrow involvement. Clinically, all patients suffered from neuropathy involving the lower limbs. In three patients, impairment was severe, making them unable to walk, while in four patients, neuropathy was moderate, resulting in patients being able to walk with crutches. Six patients had skin changes (glomeruloid hemangioma, peripheral vascular disease, sclerotic lesions, facial erythrosis, lipoatrophy and hypertrichosis). Half of the patients had an extravascular fluid overload (localized in the lower limbs in two patients, and anasarca and polyserositis in two patients). Endocrine disorders were seen in 87.5% of cases (hypothyroidism in five patients and gynecomastia in two patients). Laboratory tests revelead that the M component was predominantly immunoglobulin A (IgA) with lambda restriction (6/8 patients). VEGF level measurements
were available in six patients and were found to be elevated in all cases. Morphological examinations by computer tomography (CT) and positron emission tomography-CT (PET-CT) detected osteosclerotic bone lesions in four patients mainly located in the iliac bone, vertebrae and costal bone. Castleman disease was diagnosed in one patient. All patients received Len-Dex, with Len administered at a dose of 25 mg per day on 21 consecutive days of a 28-day cycle and Dex administered at 40 mg weekly, together with a thromboembolism prophylaxis. Two patients with localized disease underwent radiotherapy on costal and thoracic vertebrae sites. The median number of cycles was 27.5 (range 4–51). Following two cycles of Len-Dex therapy, neurological impairment was assessed as stable in five patients, while marked improvement was documented in three patients who had severe impairment at diagnosis. Gynecomastia disappeared in two patients, and polyserositis and anasarca syndrome in two further patients. Fifty percent of patients were improved for hypertrichosis, facial erythrosis and glomeruloid hemangioma lesions. Hematological response was assessed according to International Myeloma Working Group (IMWG) criteria [4] and included complete response (CR), defined as negative immunofixation of the serum or normalization of the free light chain ratio, very good partial response (VGPR), as a 90% reduction in M protein, and partial response (PR), as a 50% reduction in M protein. After two cycles of Len-Dex, one patient achieved a CR, while six patients were in PR. Figure 1 represents the response obtained for each symptom in patients after the last cycle of Len-Dex or at the time of data collection (for patients still on therapy). Neurological response was seen in seven patients, with one CR in a patient with moderate symptoms at diagnosis and six in PR, while stabilization was achieved in one patient. Three patients reached CR for skin lesions and 75% of patients had a CR for
Correspondence: Professor Mohamed Hamidou, Internal Medecine Department, CHU Nantes, F-44093 Cedex 01, Nantes, France. Tel: ⫹ 33-2-40-08-31-46. Fax: ⫹ 33-2-40-08 33-79. E-mail: [email protected] Received 18 July 2014; revised 30 September 2014; accepted 5 October 2014
1895
1896 E. Lestang et al.
F G VE
om
po
ne
nt
as tia
O
lC
yn e M
on
oc lo
na
G
em
a
an
d
co m
VF
es ng ch a Sk in
Ed
Leuk Lymphoma Downloaded from informahealthcare.com by Kungliga Tekniska Hogskolan on 08/31/15 For personal use only.
N
eu
ro p
at hy
10 9 8 7 6 5 4 3 2 1 0
complete response
stable disease
partial response (+VGPR)
progression
Figure 1. Clinical and biological responses obtained after the last cycle of Len-Dex. VGPR, very good partial response (only for M component response); VFO, vascular fluid overload.
vascular fluid overload. For all patients, a response regarding the M component was observed, with 50% reaching CR and 50% PR. Serum VEGF levels decreased in all patients except for one who progressed, and this was associated with gynecomastia. The median follow-up was 26 months (range 5.1–65 months). At the time of the last follow-up, three patients were still receiving therapy, while the five remaining patients had stopped treatment due to four main reasons. One patient was scheduled for autologous stem cell transplant (ASCT) after four cycles of Len-Dex regardless of the response. Before ASCT, he achieved a neurological and hematological partial response. Another patient experienced progression of gynecomastia with an increase in VEGF level after 18 cycles of Len-Dex, while the free light chain ratio remained normal. In this case, VEGF was a predictive factor for relapse, as the VEGF level was found to start to increase several months prior to clinical relapse. The third patient experienced a grade 3 hematological toxicity necessitating treatment discontinuation. The two remaining patients no longer receiving therapy stopped treatment after obtaining good clinical and biological responses, and they did not experience relapse for between 5 and 15 months. The following toxicities were reported: one patient developed a venous thrombotic event despite prophylaxis, diarrhea occurred in 2 patients (grade ⬍ 3) and one patient had a localized skin rash (grade ⬍ 2). Reversible cytolytic hepatitis and cholestatic hepatitis were reported in one patient. Grade 3 anemia/thrombocytopenia occurred in a patient in hematological CR and neurological PR after six cycles. Treatment was stopped in this patient, resulting in a normalization of blood count with no sign of relapse. No aggravation of neuropathy or infections was observed. Our results resemble those reported by Zagouri et al. [5] who conducted a meta-analysis of Len-Dex studies in frontline and/or relapsed POEMS syndrome (n ⫽ 51 patients).
They reported that in 12 patients treated with frontline Len-Dex, the progression-free survival (PFS) at 12 and 24 months was 93% and 47.2%, respectively. In our series, the majority of patients had improvements in neurological symptoms following Len-Dex treatment, which is a major issue in this syndrome. This clinical effect of Len has previously been described [6], and in our experience it occurred fairly rapidly with a stabilization of symptoms after only two cycles, and the majority of patients achieved a PR. Similarly, we observed a rapid resolution of vascular fluid overload, multi-serositis and anasarca. IMIDs have both anti-angiogenic and immunomodulatory properties [7]. Thus in POEMS, Len might act on symptoms caused by the hypersecretion of VEGF as well as directly targeting the plasma cell clone, wich may explain the greater efficacy of Len over anti-VEGF treatment alone [8]. Nevertheless, there is a need to further investigate treatments for POEMS, as well as to define response criteria, duration of treatment and criteria to stop treatment. In young patients with systemic disease, high dose alkylating chemotherapy and ASCT is feasible and effective [9,10]. However, taking into account the balance of benefit, risk, quality of life, data from literature and our results, the question of delaying ASCT at the time of first relapse for young patients who have reached a good clinical response with smoldering-like disease status is of interest. A prospective, multicenter phase II trial is currently ongoing in France, and will further advance our knowledge regarding treatment strategies for this rare plasma cell disorder.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Kanai K , Sawai S, Sagawa K , et al. Markedly upregulated serum interleukin-12 as a novel biomarker in POEMS syndrome. Neurology 2012;79:575–582. [2] Dispenzieri A , Kyle RA , Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood 2003;101:2496–2506. [3] Dispenzieri A . POEMS syndrome. Hematology Am Soc Hematol Educ Program 2005:360–367. [4] Palumbo A , Sezer O, Kyle R, et al. International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia 2009;23:1716–1730. [5] Zagouri F, Kastritis E, Gavriatopoulou M, et al. Lenalidomide in patients with POEMS syndrome: a systematic review and pooled analysis. Leuk Lymphoma 2014;55:2018–2023. [6] Tomas JF, Giraldo P, Lecumberri R, et al. POEMS syndrome with severe neurological damage clinically recovered with lenalidomide. Haematologica 2012;97:320–322. [7] Shortt J, Hsu AK, Johnstone RW. Thalidomide-analogue biology: immunological, molecular and epigenetic targets in cancer therapy. Oncogene 2013;32:4191–4202. [8] Dietrich PY, Duchosal MA . Bevacizumab therapy before autologous stem-cell transplantation for POEMS syndrome. Ann Oncol 2008;19:595. [9] Dispenzieri A . Long-term outcomes after autologous stem cell transplantation in patients with POEMS syndrome. Clin Adv Hematol Oncol 2012;10:744–746. [10] Gronier S, Delmont E, Legros L, et al. [Efficacy of autologous peripheral blood stem cell transplantation (auto-PBSCT) on the neuropathic manifestations in POEMS syndrome]. Rev Neurol (Paris) 2014;170:37–45.
