Brltlsh Journal ofHaernatology. 1995. 89, 191-195
`SHORT REPORT
`
`Human recombinant granulocyte-macrophage
`colony stimulating factor (hrGM-CSF)
`improves double hemibody irradiation (DHBI) tolerance
`in patients with stage I11 multiple myeloma: a pilot study
`
`X. T R O U S S A R D , l M. M A C R O , 2 B.
`A. B A T H 0 , 4 A. M. P E N Y , ' 0. R E M A N , l I. T A B A H 6 A N D M. LEPORRIER'
`'Service d'Himatologie Clinique, CHU Caen. 2Service de Rhumatologie, CHU Caen. 3Service de Radiotherapie, C.F.B. Caen,
`*Centre Regional de Transfusion Sanguine, Caen, ?Service d'Himatologie, C. F.B. Caen, and 6Laboratoire Schering Plough,
`Levallois, France
`
`Received 23 May 1994; accepted for publication 2 September 1994
`
`Summary. Double hemibody irradiation (DHBI) is an
`alternative treatment of stage I11 multiple myeloma (MM)
`in patients aged over 55 years. Toxic side-effects such as
`myelosuppression are a severe limiting factor to its use. We
`performed DHBI associated with human recombinant
`granulocyte-macrophage colony stimulating factor (hrGM-
`CSF) as support therapy in 10 patients with stage 111 MM to
`improve the tolerance to this treatment.
`Ten patients received subcutaneously 5 pg/kg/d of hrGM-
`CSF during 2 weeks after each course of hemibody
`irradiation. All these patients had stage I11 MM: eight
`them were
`previously received chemotherapy, six of
`regarded as patients with refractory MM and two with
`relapse. Two patients received DHBI as first-line treatment.
`hrGM-CSF increased safety and tolerance of DHBI.
`GM-CSF support reduced the mean time between upper
`
`body irradiation (UBI) and lower body irradiation (LBI):
`41 v 108 d in a cohort of 32 patients previously treated
`without growth factor support. Overall there was no lethal
`infection with hrGM-CSF or granulocytopenia
`(5.0 x
`109/1 v 0.4 x 109/1 at day 15 in patients without growth
`factor). hrGM-CSF also reduced stomatitis grading and
`thrombocytopenia (90 x 109/1 v 45 x 109/1 at day 15).
`Furthermore, hrGM-CSF increased blood colony forming
`unit-granulocyte macrophage (CFU-GM) and was well
`tolerated in all but one patient.
`thus
`hrGM-CSF reduces toxic side-effects of DHBI,
`providing an effective treatment in patients with advanced
`and resistant MM.
`
`Keywords: multiple myeloma, double hemibody irradiation,
`human recombinant GM-CSF.
`
`Treatment of patients with advanced multiple myeloma
`(stage III in the Durie and Salmon staging) is a dacult
`challenge. Median survival, disease-free survival, response
`rate and analgesic effects must be considered in therapeutic
`assessment. Little progress has been observed following the
`introduction of alkylatiig agents. In patients with de novo
`MM, multi-institutional controlled trials failed to show a
`therapeutic advantage of various multidrug regimens when
`compared with melphalan and prednisone (MP) (Gregory
`et al, 1992). In patients with refractory MM median survival
`is short with chemotherapy including vincristin, adriamycin
`and dexamethasone (VAD regimen), or cyclophosphamide
`
`Correspondence: Dr X. Troussard. Service Hbmatologie, CHU
`Clemenceau. 14033 Caen Cedex. France.
`
`and etoposide or high-dose melphalan. Toxicity and
`mortality caused by severe myelosuppression are the main
`limiting factors, and the quality of lie of these patients is
`very poor.
`Multiple myeloma is radiosensitive: Bergsagel (1971)
`estimated that lOGy would reduce the turnour mass by
`3 log. Recent progress has been obtained with autologous or
`allogeneic bone marrow transplantation using, in most
`cases, total body irradiation as conditioning regimen. An
`alternative radiation therapy is double half-body irradiation
`(DHBI). It has been shown in dogs that a single-dose
`irradiation of hemibody is followed by a recirculation of stem
`cells and repopulation of the irradiated bone marrow within
`15-20d (Nothdurft et al, 1984. 1989). These observations
`support the concept that DHBI could be an equivalent of
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`192 Short Report
`autologous bone marrow transplantation without the
`requirement of peripheral stem cells collection.
`DHBI has been proposed for the treatment of solid
`tumours. lymphomas and MM o d e et al, 1979). We
`previously reported the long-term results of DHBI in 32
`patients without hrGM-CSF showing similar results when
`compared to conventional protocols (Troussard et al. 1988;
`Troussard & Leporrier, 1991). In 19 patients DHBI was the
`first-line therapy: all these patients had stage 111 MM and
`bone pain unrelieved by major analgesics. The overall
`median survival was 25 months and the analgesic effect
`obtained had a mean duration of 15 months. In this series
`we obtained two complete remissions (CR) with a relapse 30
`months after DHBI and a persistent CR 15 months after
`irradiation. However, tolerance of the two consecutive
`irradiations was poor, with severe pancytopenia in 44% of
`patients. Four patients died from infection 3 months after
`DHBI: one septicaemia. one tuberculosis and two pulmonary
`infections. DHBI also induced severe stomatitis in all cases.
`We also reported the results in 13 patients with primary
`resistant or relapsing MM treated with DHBI as second-line
`treatment: analgesic effect was present in all but one patient
`with a mean duration of 5 months: the overall median
`survival was 6 months, comparable to the VAD regimen.
`In the present pilot study we treated 10 patients with
`DHBI, and hrGM-CSF support to reduce toxic side-effects
`of irradiation.
`
`MATERIALS AND METHODS
`Patients. 10 patients underwent DHBI with hrGM-CSF for
`stage III multiple myeloma according to the clinical staging
`system of Durie & Salmon (1975).
`The diagnosis of MM was established when at least two of
`the following criteria were present: (1) a paraprotein
`detectable in serum of urine, (2) >lo% plasma cells in
`bone marrow, and (3) osteolytic and/or osteoporotic bone
`lesions compatible with MM. Primary resistant or relapsing
`MM was defined when one or more of the following criteria
`were fulfilled: (1) at least a 25% increase in the serum M
`component concentration when compared with the pre-
`treatment or pre-response value: (2) a 100% increase in 24 h
`urinary Bence Jones protein excretion when compared with
`pre-treatment or pre-response value: (3) serum calcium
`>3 mmol/l, and/or (4) progression of osteolytic lesions.
`Eight patients received chemotherapy as first-line treat-
`ment: all the patients received MP and two patients received
`VAD or VMCP-VBAP regimen in cases of primary resistance
`or relapse. Out of eight patients, six were progressive and two
`relapsed, with one patient resistant to MP. Chemotherapy
`was given for a mean of 24 months (13-52) with a mean
`number of cycles of 12 (8-19). Two patients underwent
`DHBI as first-line treatment: both had hypercalcaemia and
`elevated serum /32 microglobulin at diagnosis.
`All the patients gave their written informed consent.
`Double hemibody
`irradiation
`(DHBI). As previously
`described (Troussard et al, 1988; Troussard & Leporrier,
`1991), total body irradiation, delivered by a Sagittaire
`25MeV linear accelerator, was given in two stages of
`
`hemibody irradiation separated by a mean interval of 7
`weeks. The border between UBI and LBI was arbitrarily fixed
`at the umbilicus. The patients were placed in a dorsal
`decubitus position and a single divided dose was delivered by
`equal anterior and posterior beams. A dose of 8Gy was
`delivered with pulmonary and buccal protection after
`6.5 Gy. The starting rate was 50 cGy/min and the mean
`session time was 15 min. The upper body was treated fist
`because it was usually the more painful. Prior to each
`session anti-emetics were given to prevent nausea and
`vomiting. The second irradiation was not given until the
`granulocyte count reached 1.5 x 109/1 and the platelet
`count reached 100 x 109/l. Blood cell counts were performed
`weekly until the appropriate values were obtained.
`Human recombinant granulocyte-macrophage colony stimu-
`lating factor (hrGM-CSF). hrGM-CSF (Schering Plough,
`France) was delivered at a dose of 5pg/kg in a daily
`subcutaneous infusion from day 0 to day 15 after UBI and
`LBI. Potential side-effects were clinically recorded and
`graded according to the W.H.O. classification.
`Peripheral
`and
`bone-marrow
`granulocyte-macrophage
`progenitors (CFU-GM) studies. The CFU-GM were cultured
`using the technique initially described by Pike and Robinson.
`The results were expressed as the number of colonies per ml
`of peripheral blood.
`Response criteria. Response criteria were those used by the
`Southwest Oncology Group.
`
`RESULTS
`Ten patients, seven males and three females, with a mean
`age of 63 years (49-71), were entered into this study. All
`patients had stage IIIA MM at the time of DHBI. The mean
`time between diagnosis of MM and DHBI was 26.3 months
`(2-63). The first-treated hemibody was upper body in four
`and lower body in six patients. Out of 10 patients, nine
`received the complete treatment. The analysis was updated
`in January 1994.
`
`Toxic side-effects
`We compared the toxic side-effects with a historic cohort of
`32 patients treated without hrGM-CSF support.
`Huematological toxicity. The pre- and post-DHBI blood
`counts of patients treated with hrGM-CSF are shown in Fig 1.
`As expected, neutrophils. eosinophils and monocytes were
`sustained during the 2 weeks with hrGM-CSF. The changes
`over time are also shown in Fig 1. For the first hemibody the
`mean neutrophil count was. respectively, 2.7. 4.5, 7.7 and
`2.9 x 109/1 before and at days 8, 15 and 21 after
`irradiation, compared to 2.4, 1.2. 1.0 and 0.8 x 109/1 in
`patients without hrGM-CSF support (Table I). For the second
`hemibody the mean values were 2.8, 3.0, 5.0 and
`1.9 x 109/l. As a consequence, no infection was detected,
`compared to 11 in the group without GM-CSF. Thrombo-
`cytopenia was obvious in all patients: platelet transfusions
`were required in 7/9 treated patients with a mean number of
`transfused platelet units of six per patient.
`The mean time between UBI and LBI was 41 d (28-50).
`No irradiation was delayed in patients treated with
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`
`19 3
`
`b )
`
`2 0
`
`1 5
`
`1 0
`
`5
`
`1 5
`
`A 2 2
`? 1 0
`v
`0
`L
`4
`
`5
`
`1 . 3
`0
`
`
`
`d l
`I
`
`d 8
`
`d 15
`1
`
`d 21
`day after HBI
`
`
`
`d l
`I
`
`d 8
`
`d 15
`1
`
`d 21
`day after HBI
`
`rhGM-CSF
`
`( 5 v g / k g / d )
`
`rhGM-CSF
`
`( S v g / k g / d )
`
`Fig 1. Granulocyte counts after first (a) and second (b) hemibody irradiation (HBI) in patients with rhGM-CSF support.
`
`hrGM-CSF. In contrast, 13 patients received UBI or LBI
`10-18 weeks after the first irradiation.
`Other toxicities. hrGM-CSF was well tolerated except by
`three patients who reported a slight exacerbation of bone
`
`pain: however, it was difficult to distinguish between bone
`pain related to MM and/or a toxic side-effect of hrGM-CSF.
`Eventually, pain decreased in all patients after completion of
`hrGM-CSF treatment, and major analgesics were stopped in
`
`Table I. DHBI in patients with and without hrGM-CSF support.
`
`MM-CSF:
`
`Absent
`
`Present
`
`No. of patients
`DHBI as bt-line therapy
`DHBI as second-line therapy
`Time Dg/DHBI (months)
`Monoclonal Ig (g/l)
`p 2 microglobulin (pg/l)
`LDH (U/U
`Median granulocytes ( x 1 O9 /I)
`after first hemibody irradiation
`Day 0
`Day 8
`Day 15
`Day 2 1
`Median time (days) between
`UBI and LBI
`~ e d i a n granulocytes ( x 109/1)
`after second hemibody irradiation
`Day 0
`Day 8
`Day 1 5
`Day 21
`Treatment achieved
`
`32
`19
`13
`8
`43
`4
`142
`
`(1-37)
`(16-74)
`(1.2-7.1)
`( 1 10-3 10)
`
`2.4
`1.2
`1.0
`0 8
`
`(0.6-6.3)
`(0.0- 1.4)
`(0.0- 1.4)
`(0.2-2.1)
`
`10
`
`8
`26
`30
`6
`255
`
`2.7
`4.5
`7.7
`2.9
`
`(2-63)
`(7-54)
`(3.2-8.5)
`( 1 54-400)
`
`(0.5-5.9)
`(0.7-104)
`(1.3-1 6.7)
`(0.6-6.4)
`
`108
`
`(28-482)
`
`4 1
`
`(28-50)
`
`2.0
`1.1
`0.4
`0.5
`25
`
`(0.7-5.9)
`(0.03-1'6)
`(0.03-04)
`(0.1- 1.6)
`
`2.8
`3.0
`5.0
`1.9
`9
`
`(007-5.4)
`(004-6.9)
`(08- 1 4 7)
`(05-5.6)
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`194 Short Report
`all cases. Exacerbation of a previously diagnosed supra-
`ventricular anythmia was observed in one patient after 13 d
`- hrGM-CSF treatment was discontinued and the second
`hemibody irradiation was not performed. Stomatitis was
`observed in all cases but was of only grade I with hrGM-CSF
`as compared to grade 4 in patients without growth factor. In
`addition, hrGM-CSF had no influence on non-haemopoietic
`DHBI-related toxicity (nausea, vomiting and alopecia).
`
`Follow-up
`The overall follow-up was 11 months (2-33): 7.5 months
`(5-1 3) in patients with a previous chemotherapy treatment
`and 24 months (18 and 30) when DHBI was used as first-
`line treatment. 5/10 patients died from refractory MM at 2.
`5, 6, 6 and 11 months after the completion of DHBI.
`Interestingly, these patients had reduced bone pain at the
`time of death. Five patients are alive at 35, 22, 17. 8 and 5
`months after treatment.
`
`Tumour response
`In two patients with de novo multiple myeloma we observed
`one RC, with a relapse at 33 months treated by VAD
`regimen, and one very good response persistent at 22
`months. In the eight patients receiving DHBI as a second-line
`treatment we obtained seven partial responses with a
`decrease of M component from 45% to 85% and one
`minor response.
`
`Blood CEU-GM before and afkr DHBl
`After the first hemibody irradiation (eight patients tested)
`mean peripheral blood CFU-GM increased from 12 CFU-
`GM/ml before irradiation to 3 5 CFU-GM/ml at day 15 after
`the first hemibody irradiation. This increase was obvious in
`three patients, whereas in two additional patients peripheral
`CFU-GM reached the pre-irradiation values. No beneficial
`effect was observed in three patients.
`After the second hemibody irradiation (six patients tested)
`the mean peripheral CFU-GM rose from 5 to 17 CFU-GM/d
`at day 15. The increase was dramatic in three patients and
`in two additional patients peripheral CFU-GM reached pre-
`irradiation values. In contrast, this effect was not observed in
`three patients who underwent DHBI without hrGM-CSF.
`
`DISCUSSION
`DHBI is regarded as an alternative treatment for patients
`with advanced stage 111 MM (Jaffe et al, 1979). In a
`prospective and randomized trial DHBI was ineffective as
`consolidation treatment in patients who achieved remission
`after VMCPIVBAP chemotherapy (Salmon et al, 1990). In
`contrast, we showed in 18 patients treated with DHBI as
`first-line therapy an overall median survival of 25 months
`(Troussard & Leporrier. 1991). However, the main limiting
`factor was haematological toxicity, which was observed
`in eight patients (44%). In patients non-responsive to
`chemotherapy, or in relapse, we and others showed that
`DHBI-related myelotoxicity is clearly higher (Jaffe et al.
`1979: MacKenzie et al, 1992: Singer et al. 1989: Rostom
`et al, 1984). In 41 patients with melphalan-resistant MM,
`
`pancytopenia occurred in all patients with a nadir within 3
`weeks after hemibody irradiation: myelosuppression was
`more pronounced after the second procedure as reflected by
`blood product requirements (Singer et al. 1989). In this pilot
`study we showed that hrGM-CSF associated with DHBI
`reduced the haematological toxicity when compared to 32
`patients receiving DHBI without rhGM-CSF support. First,
`neutrophil granulocytes counts were sustained during the 2
`weeks and after the completion of hrGM-CSF treatment. In
`contrast, in the group without hrGM-CSF granulocytopenia
`was severe and protracted in all patients, with a mean nadir
`at day 21 for the first hemibody irradiation and at day 35 for
`the second hemibody irradiation. Secondly, four severe
`infections occurred in the 18 first-line (22%) and seven in
`the 13 second-line (54%) DHBI-treated patients without
`rhGM-CSF support, whereas we did not record any infection
`in patients with rhGM-CSF. In addition, we observed a
`significant reduction of the mean number of transfused
`platelet units (6 versus 15 in patients without rhGM-CSF
`support). hrGM-CSF reduced median time between UBI and
`LBI: 4 1 d (28-50) in the group with hrGM-CSF compared to
`108 d (28-482) in the group without hrGM-CSF. All but one
`patient achieved complete treatment, compared to only 50%
`of patients without rhGM-CSF (Jaffe et al. 1979: Troussard
`et al, 1988, 1991: MacKenzie et al, 1992: Singer et al, 1989;
`Rostom et al, 1984). This effect could be of clinical relevance,
`because achieving complete treatment and decreasing
`the mean interval-time between UBI and LBI could result in
`a better objective response and prolonged disease-free
`survival as well as overall survival in selected patients
`(Singer et al, 1989).
`Non-haematological toxic side-effects were dramatically
`reduced by rhGM-CSF: severe stomatitis was observed in all
`cases with DHBI but was of grade I in rhGM-CSF-treated
`in patients without
`patients, compared to grade 111-IV
`growth factor support. Jaffe et a1 (1979) also noted severe
`stomatitis, requiring hospitalization in 2/11 patients: they
`then employed an anterior cavit shield in following patients.
`hrGM-CSF acts as a potent growth factor both in vitro and
`in vivo assays: it stimulates proliferation and maturation of
`myeloid progenitor cells, enhancing neutrophilic and
`eosinophilic granulocyte counts as well as monocyte
`counts. To our knowledge, hrGM-CSF has never been used
`after DHBI. Many of
`the proposed therapeutic uses
`emphasize the ability of hrGM-CSF to allow higher drug
`dosage in cancer treatment and bone marrow transplanta-
`tion. It has also been reported to reduce the duration of
`neutropenia and the severity of infections. An explanation
`of the shortening of mean time between UBI and LBI could be
`that hrGM-CSF increased peripheral CFU-GM at day 15 after
`the first and second hemibody irradiation. Experimental data
`in dogs showed that a 11.7Gy irradiation of the upper
`hemibody was followed by an increase in the proliferation
`and differentiation of granulocyte-macrophage progenitor
`cells (GM-CFC) in the protected bone marrow (Nothdurft
`et al, 1989). Repopulation by the GM-CFC of the irradiated
`sites from the protected bone marrow became evident at day
`7 after UBI and at day 2 1 after LBI. Within 3 70 d all the bone
`marrow irradiated sites had regained their normal GM-CFC
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`values. In our patients hrGM-CSF clearly increased the mean
`peripheral CFU-GM at day 15: from 12 to 3 5 CFU-GM/ml
`after the first hemibody irradiation and from 5 to 17 CFU-
`GM/ml after the second hemibody irradiation. Unfortunately
`we were unable to demonstrate an increase in bone-marrow
`CFU-GM with either protected or unprotected or first or
`second hemibody irradiation.
`The role of cytokines in the growth of myeloma cells has
`been investigated previously. Paracrine or autocrine regu-
`lation of the growth and differentiation of myeloma cells by
`IL-6 has been suggested in vitro. The effect of hrGM-CSF is
`debatable: no significant proliferation of plasma cells was
`noted following hrGM-CSF, G-CSF. M-CSF, &la. IL-lb, IL2
`or IL-4 treatment (Anderson et al, 1989). In contrast,
`significant proliferation was induced by IL-3 or IL5
`(Anderson et al. 1989). Another study showed that hrGM-
`CSF was a strong stimulator of in vitro myeloma cell
`proliferation by potentiating the response of myeloma
`cells to IL6 (Portier et al, 1993). The clinical relevance
`of these in vitro findings remains to be c o h e d , when
`GM-CSF is employed in multicentre trials to improve
`peripheral blood apheresis in autologous bone marrow
`transplantation. Interestingly, in our study we did not
`notice any apparent stimulating effect of the hrGM-CSF on
`bone marrow myeloma cells: nor did we record any M
`component increase following hrGM-CSF.
`
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