9. Aggressive lymphoma
557 558
PROGNOSTIC FACTORS FOB ADVANCED STAGE. INTERMEDIATE
CLINICO-PATHOLOGIC FEATURES OF K M POSITIVE, ANAPLASTIC LARGE AND HIGH GRADE NON-HODGKIN LYMPIIOMAS.
CELL LYMPHOMA IN EGYPT.
DA Gribabh, ThP VraOakopoulo*, VA Boimtotlj. F Komopldou, Ch Kltlas. GA
F-Abot-Ba. H.Khated, H.Taha, M.N.B-Bolkainy, R.Gaafar, MJUidei-Mooti, B.Bedair ; Pangafa. Hm Dipartment of Internal M«Bdn*, National and KapodJariaii
Pathology and Medical Oncology Depti., National Cancer Institute, Cairo, Egypt Unhvntfy o( Athens, Lalkoa Gsxral Hospital, Alhem, Greece.
K H positive, Anaptestic Large Cell Lymphoma (ALCL), has distinct cflnlco-parthotoglc Advanced a m (IIVTV) autnntdlati (K3> and high qrada (HG) non-Hodgklii
features which can resemble many other conditions. In this study, retrospective tymphomat (NHL) arc not curable wUh the convmUonaJ chemotherapy regimens.
analysis of 2 groups of patients was done. The first group included children and young In about the half of the patients (pts). Several rlafflflmtlnn s^wtems based on
adults presenting wfth lymphadenopathy and primarily diagnosed as metastaUc prognostic factors (PF) have been developed In order to distinguish subgroups of
patients utih poor prognosis, who are probably cfigfUe to participate In aggressive
undifferentiated carcinoma, while the second group consisted of patients diagnosed as chemotherapy protocols, followed by peripheral blood stem cell rescue or bone
high great lymphoma. Cases were selected on basis of peculiar involvement known marrow transplantation. In the present study we analyzed 174 pts wtth stage III or
for ALCL K M positive lymphoma. Twenty-six cases in each group were studied by IV, )G or HGNHL (etcept of lympboblastlc and dlfiuse small non-ckaved cell
NHL), aiming to identify prognostic factors (PF) for achievement of complete
immunophenotypic markers Including LCA, UCHL1, Leu 4, EMA, Cytokarattn and Ber remission (CR) and survtvaL The parameters studied were age ( s 6 0 vs >60
H2. Among the first group 8 cases showed the profile of ALCL K M positive years), gender, performance status (PS: 0-1 vs 2-4), stage, B-eymptoms, botic
lymphoma. Their ages ranged between 13 and 40 years, with a median of 29 years, 5 marrow Involvement (BMI), number of Involved cxtranodal sites (O-l vs i2>,
hWologlc subtype, serum LDH levels (nomud vs Increased), ESR (4JO, 21-50,
males, 6 presented with localized and 2 with generalized lymphadenopathy. >50) and serum albumin levels (2
group received regular treatment protocols and 4 received local radiotherapy to sites cxtranodal sites, m inulilvariale analysis. Moreover, In ntulltvariaia analysis of PF
for OS, only age >60 years had Independent prognostic significance. Whh respect
of disease. Complete remission was achieved in 8 out of the 15 K M postttve cases, to the modmed IPI, no differences were observed for CR rales. Patients wllh only 1
with a median overal survival of 16 months. Durable second remissions were also adverse PF had better DFS than those with 3-4 |p=0.02) and better OS than both
achieved In some of the relapsed patients. So, In conclusion, apart from the role of W- those with 2 (p-0.08 borderline) and 3-4 (p-0 03) adverse PF. Our results are
generally consistent with recent targe mulllcenler studies and confirm the abfllty to
1 antigen in differentiating this type of tymphoma from morphologically similar dlsartmljuue pts with advanced IG or 1-tG NHL with poor prognosis, m order lo be
conditions as undifferentiated metastatic carcinoma, K M positive NHL should receive treated more aggressively.
more intensive chemotherapy protocols to improve their CR rates and to benefit from
their tendency to attain durable second CR.
559 560
IS THE DOSE INTENSITY AN INDEPENDENT ANALYSIS OF PROGNOSTIC VALUE OF P53 AND PCNA EXPRESSION A D N
TRANSLOCATION t ( 1 4 ; 1 8 ) IN HIGH-GRADE NON-HODGKIN'S L M IO A Y PI M
PROGNOSTIC FACTOR FOR SURVIVAL IN HIGH-GRADE 1 2 1
A. Fossa ", K.A. Metz *, R. S i e b e r t * , C.P. W l l l e r s \ U. Noser 2 ,
MALIGNANT NON-HODGKIN LYMPHOMAS? B. Opalka 1 , S. Seeber1, M.E. Nowrouslan 1 ('contributed
equally).
0 . Sezer, K. Taghizadeh and H. Rasche. 1 2
Departments of Medical Oncology and Pathology , University of
Department of Internal Medicine I, Zentralkrankenhaus Essen, Essen, PRO
St.-JQrgen-StraBe, 28205 Bremen, Germany Molecular and cytogenetic findings have been reported to be
associated with clinical features and treatment response in
150 patients with high-grade malignant non-Hodgkin's non-Hodgkin's lyaphoaa (NHL). He studied p53 and PCNA
lymphoma were treated in a single centre with CABOPP, a expression by iuunohistochealatry and the translocation
modified COPBLAM protocol ( cyclophosphamide 500 mg/m2 t(14;18) by PCH in 36 patients (pts) with de novo high-grade
non-lymphoblastic NHL according to the Kiel classification. All
(iv) dl, doxorubicin 50 mg/m2 (iv) dl, bleomycin 3x1 mg (sc) pts were uniformly treated with an anthracycline-containing
dl-5, vincristine 1 mg/m2 (max. 2 mg, iv) dl+8, procarbazine •ultiagent cheaotherapeutic regimen.
100 mg/m2 (po) dl-10, prednisone 50 mg/m2 (po) dl-10 ). In The aedian age was 48 years (19-66). 5 pts had clinical stage
(CS) I, 17 CS II, 5 CS III and 9 CS IV disease. LDH > 240 U/l
patients older than 70 years the dose of cyclophosphamide and was present in 20 pts, B-syaptoas in 18 pts, and extranodal
doxorubicin were reduced to 300 mg/m1 and 30 mg/m2, Involvement in IS pts.
693 (22/36) of the pts achieved coaplete remission (CR) and 31X
respectively. The median age was 56 (range: 19 - 90). 72 % of (11/36) failed to respond or died during therapy. With a eedian
the patients achieved a complete remission with CABOPP. follow up of 9,5 aonths, the projected survival for the whole
group of pts is 58X at 34 months. 80X of the responding pts are
The chemotherapy associated mortality was 2 %. The overall predicted to readln free froa progression at 32 months.
survival rates were 65 % at 3 years and 45 % at 5 years. By p53 expression defined as positive staining in i. 40X of tuaour
multivariate analysis the major risk factors for the overall cells was found in 17/36 pts. In 24/36 pts i. 80X of tuaour
cells stained positive for PCNA. Molecular evidence for
survival were performance status, age and serum lactate t( 14; 18) was found in 22/34 cases. Multivariate analysis
dehydrogenase concentration. Neither the received total dose confirned CS as the sole prognostic factor for achleveuent of
CR and for survival. Other clinical parameters, expression of
of chemotherapeutic drugs nor the relative dose intensity p53 and PCNA and occurrence of t(14;18) did not appear to
calculated by incorporating the duration of the actual correlate with clinical outcome.
treatment courses were independent prognostic factors for the
survival in the multivariate analysis.
9. Aggressive lymphoma 151
561 562
PROGNOSTIC FACTORS IN PATUMTS WITH OBTUSE IAHGE CHI NON- PROGNOSTIC SIGNinCANCE OF IMMUNOPHENOTYPE IN
HOOGKNS LYMPHOMAS (NHL). INTERMIDIATE AND HIGH GRADE NON HODGKINTS LYMPHOMAS.
A HaiB*IC CO-OPttATTrt ONCCXOGY GKXJP STUDY
CMcoUd.1, CFourtrfcs. KLZouoboi. D.Sldfcii. P. Koiakii. K. Stefanoudaki-Soflanatou1*, P. Repouslsl*, Th. Papadaki 2 , M. Bakiri1,
AJCaraUS., TKOamaUdi, ASymmidl, LEtommou, KPovW.. M. Niklforakis1, D. Anagnostou 2 , A. Papayiannis 1 .
hWCOG OHlc, M.«>glon M. IB 27 Alt-ra, G , « c .
Haemntology 1 and Haematopathology 2 Departments,
Aim oiW NW«rkitr In Ihb retrotptcthre nufelurtric tfudy t U paiilJ* Evangelismos General Hospital, Athens - Creece.
prognostic voxiobfai for tumor r*tpora«, (ftMai* Inm curvtvd and ovaroQ ''Present address; HaematologyDptofSt.Anargyri Cancer Hospital, Athens-Greece.
•urvfvd w.r» anojywd in 215 conMcullvWr (rooted pollonts wth dtfh/u lorga
c*0 NH. (WF uttypn G and r". Sixty it* pollonU |3I%| praMrttd w*ti
primary •Jdranodol i t w m . Two hundred ihra* pdkrti (94.4%| w«r« Ireohd
Controversy exists regarding the prognostic significance of
wth adrknydn baud hi, 2nd and 3rd gmroikai rogknoni. M«Jon lolow up immunophenotype in intermldiate and high grade (I-HG) non Hodgkin's
w n 18 months. Lymphomas (NHL). To evaluate the significance of B JO mrVK oburah i3-So/ slgnllcont voriabbi. comparison between curves were based on the log-rank test. Statistical
(c]For dlMci* frw turvfvd both In th* untvarlot* anotysb ai w«l oi h analysis used the X2 test and Fisher's exact test for comparisons of groups.
awtlpU Cox analyiii PS23 and a>aU gmaW wrf. l U iwgoliv* proa^oiHc Cox's proportional hazards model was used to assess the prognostic value
ladori. of factors on survival and DPS in a multivariate framework. 68 cases (75%)
(d) In tK« unfvoriol« anatyill voriabUt prsdkling turvival w«r«- PS, slog*. were classified as Bronodol dU«OM, unlnvolvad bon* marrow, ipU«n invoryw—nt, tn« (ALCL). There was an even distribution of clinical characteristics
nnb*f ol .xlronodd tilai ol dluow, fi-rympleani, IDH, obumkv htnuuloHn between the two groups except for B symptoms which had a high
Downloaded from http://annonc.oxfordjournals.org/ by guest on January 2, 2012
and ESI In th. mMpU Cox oWy.ii PS 23 (p-O.OOOO) stag. Ill-TV (p-0O24a) incidence on T-cell lymphoma pts (p 07). The pts with T-cell lymphoma
and ESB >50 (p-00071) w«r« ubct«d ai prognodk lodo»i showed worse DFS comparing to those of B-cell (27% v 65%) at 5 yrs with a
{•) No staHdkal aW«nnc* wai o l u m d ilhif h conpUl* rctpou* rat« median of 23 m for the first group, median for the second group of pts not
|p-0-2509) nor In ovtral •urvt«al |pHDJ3V5) bdwmi Ir«atmn4 gmranon reached yet. Overall survival was 21% for T cell vs 42% for B cell
lymphoma at 5 yrs (p.064). Multivariate analysis revealed age, Karnofsky
status, LDH and initial response to treatment as the most important factors
affecting survival for both groups of pts. We conclude from our study that
more aggressive front line treatment should be considered as therapy for at
least some pts with T-cell NHL, I and HG malignancy.
563 564
DETECTION OF IgH AND IgL REARRANGEMENTS IN INTERMEDIATE Impact of Prognostic Factors and Long Term Results of BECOP
AND HIGH GRADE B-CELL NON HODGKIN'S LYMPHOMAS Regimen in Aggressive Non HodfWn Lymphoma.
Hussein M. Khaled ,N.G«d El-Mawla, M.R.Hamm, M.N.El-Bolkairry,
Nico van Belzen' lJ , Pauline E. Hupkes 11 , Marianne Hoogeveen 12 ,
R. Gaafar, N.Mokhtar ,1. El-Attmr, and I. Magrath • . * National Cancer
Lambert C.J. Dorssers1, and Mars B. van 't Veer'. 'Dept. Hematology,
Institute, Bethesda, MD ,USA , and National Cancer Institute, Cairo .Egypt
Dr. Daniel den Hoed Cancer Center, P.O.Box 5 2 0 1 , 3008 AE
Rotterdam; and 2 Dept. Hematology, Erasmus University, Rotterdam, Malignant Lymphomasrankthird (- 10 %) among patients presenting
The Netherlands. to the NCI of Egypt, with a higherfrequencyof aggressive subtypes and
advanced disease stages at presentation.
Rearranged IgH genes provide unique clonal markers for B cells, and In this study, a modified BECOP regimen were given every 3 weeks
allow sensitive detection of low levels of neoplastic B cells by PCR. rather than a 4 week period with a 25 % increase in dose intensity more than
However, cloning of the rearranged gene and proving that the cloned the standard BECOP combination , i.e. vincristine 1.4 mg/sq.m.,epinibicin
sequence is indeed derived from tumor cells appears to be more 40 mg/sq.m., cyclophosphamide 650 mg/sq.m., all IV days I & 8 .bleomycin
lOu/sq.m. IV day 15 , and prednisone 60 mg/sq.m. POdays 1 5 - 2 1 .
problematic in non Hodgkin's lymphoma (NHL) than in other B cell
One hundred and eight adult NHL patients were included in the study .
malignancies. We have therefore used a comprehensive PCR primer set
Seventy six were males .and 32 were females, with a M/F ratio of 2.4/1.
and stringent selection criteria to identify tumor-specific rearranged IgH
Their ages ranged between 16 and 70 yean (median 42 years ). Eight)'
genes. Lymphoma DNA was subjected to PCR using consensus JH 1
two(76%) patients had grade II and 26 (24%) had grade 1 1 pathologic
primers and either consensus VH or VH-femily specific primers. The subtype. Eleven (10%) patients presented with stage 1, 19 (18%) with stage
cloned IgH rearrangements are considered to be of tumor origin if the II. 64 (59%) with stage 111, and 14 (13%) with stage IV disease. The number
PCR products are predominantly monoclonal (as determined by direct of courses given ranged between I and 9 (median 6 ). Complete and partial
sequencing or denaturing gradient gel electrophoresis, DGGE), and if remissions were achieved in 79 (78%) and 10 (10%) out of 101 evaluabie
the same sequence is amplified with two independent VH primers. Of patients. Acturial 3-year overall and disease-free turvival rates were 55 %
13 intermediate and high grade malignant NHL, 12 yielded a PCR and 50 % respectively. Toxicities were mostly of grade 1 and II, with 5 %
product with two independent primers; 11 of these are considered mortality of treatment complications.
tumor-derived. The rearranged sequences showed 83-99% homology Response rates and survival data of this group of patients were analysed in
with their VH germline counterparts. In some cases clonal sequence relation to age, LDH level, rumor burden, and disease stage at presentation,
heterogeneity was observed. as well ts to the international index and the received dose intensity .
While this more dose intesive BECOP regimen has achieved the best
Using a patient-specific primer chosen in the CDR3 region of the results reported for treatment of adult NHL patients in Egypt, an ongoing
rearranged IgH gene, minimal residual disease was detected in study is evaluating the role of continuous infusion chemotherapy ( EPOCH
peripheral blood samples of a lymphoma patient. regimen) as front line therapy in previously untreated NHL patients.
Since accuracy is of utmost importance in diagnosis, rearranged IgL
genes are being cloned from lymphoma DNA to use as a second
marker for minimal residual disease.
152 9. Aggressive lymphoma
USE OF THE INTERNATIONAL PROGNOSTIC INDEX CENTRAL NERVOUS SYSTEM (CNS) RELAPSE IN NHL: INCIDENCE, RISK
(IPI) AND THE TUMOR SCORE (TS) TO DETECT POOR- FACTORS AND VALUE OF PROPHYLAXIS.
RISK PATIENTS WITH PRIMARY MEDIASTINAL JC Kluin-Nekmans, E Bollen 1 , RE Brouwer, S Hamers1, PM Kluin1, J.Hermans'. Dcpu of
LARGE B-CELL LYMPHOMA (PMLCL): A STUDY WITH Hcmuology, 'Neurology. 'Pathology and 'Medical Statistics, Leiden University Hospital.
37 PREVIOUSLY UNTREATED PATIENTS. J.E. Romaguera, Leiden, The Netherlands.
J. Rodriguez Diaz-Pavon, LCarias, F.B. Hagcmeister, P. McLaughlin, ID a retrospective analysis, the incidence, risk factors and potential role of prophylaxis
M.A. Rodriguez, A.H. Sarris, A. Younes, A. Preti, Edio LJerena, and of secundary CNS relapse were studied in 553 patients (307d ;2469. median age 59.2 yr) with
Fernando Cabanillas. The University of Texas M. D. Anderson Cancer NHL seen in our institution between 1983 and 1990.
Center, Department of Hematology, Lymphoma Section, Houston, Tx, Methods: Patients with AIDS. CLL and ALL were excluded. Diagnosis of CNS involvement
U.S.A. The best therapeutic approach and prognosis for patients with was made on spinal fluid analysis, mydofraphy, CT or MRI scans, brain biopsies, or a
PMLCL is undetermined. New prognostic models devised for combination of rhese. Risk factors assessed were: age. sex, malignancy grade (according to
intermediate grade h/mphomas might not apply to PMLCL in view of its the Working Formulation), stage, localizatioa, response to initial therapy. CNS prophylaxis
different biological features [e.g. their B2 mkroglobulin (b2M) is consisted of MTX i.L, high dose ARA-C consisting regimens, or both. CNS relapses were
consistently lower than other types]. Patients and Methods: We tested treated by MTX i.t. and whole brain radiotherapy with deiamcthasone in most ewes.
the age-adjusted IPI (aalPI) and a modified TS (MTS) in which the Results: Out of 553 patients, 21 bad primary cerebral NHL and were excluded. Eleven patients
prognostic threshold value of b2M was lowered to 1.6 mg/dl which was presented at start with both CNS and systemic NHL. With a median follow-up of survivors
the median value of our studied population. Thirty-seven consecutive of 30 months, another 55 patients developed CNS relapse, making up for a total cumulative
untreated patients diagnosed with PMLCL and treated from January risk of 19% at 4 year. Of these 55, 9 piescutcd initially with low grade (4 of whom had
1985 to January 1994 at our institution were included in the analysis. progressed to a higher grade), 33 wirh intermediate grade, 9 with high grade and for 4 cases
Results: Thirty-two percent of the patients fell in the low-risk category no WF grading was available. CNS relapses were localized lcptomeningeal ( n - 2 6 ) ,
according to the aalPI and 43% of the patients presented with a low parenchyma] ( n - 5 ) or both (n—21). Median tune between initial NHL diagnosis and CNS
score according to the MTS. Only the MTS predicted for achievement of relapse was 9 months (1-97), with all high grade cases having their relapse within the first 24
complete response (93% versus 60% for low and high scores, months; in the others relapses were seen up to 6-8 years after diagnosis. Risk factors for CNS
respectively; p = 0.02). Both models defined a group of patients at high relapse were malignancy grade, age e was
for refusal). Results: The complete response (CR) rate was 98% (49/50); 1 (2%) reported as definitely T cell in 11, possibly T cell in a farther 4, I) cell In 2 and w n
patient showed a progressive disease to CNS during CHOP chemotherapy and died indeterminate in Ibc remainder.
for lymphoma. Six patients (12%) in partial remission after CHOP achieved CR
following involved Odd radiotherapy. After a median follow-up of 39 months, 4/49 Seven children did not achieve a complete rcmistioo on this regimen, five of whom have
patients have relapsed, three of these patients relapsed in the she of previous died (two responded when changed to a Hodgkin'i type regimen). Of the remaining 27
radiation therapy. The actuarial 4 years overall survrtal and event free survival was children who did respond In initial treatment 19 remain in complete remission with a
respectively 88% and 81%. The treatment was well totalled without significant median followup of Iwcoly four months (range 3 - 5 2 moaths). Seven children have
Downloaded from http://annonc.oxfordjournals.org/ by guest on January 2, 2012
usddty. Conclusions :Short course of CHOP chemotherapy followed by involved rdapscd of whom six have died. One child died of secondary leukaemia.
field radiation therapy is a safe and effective treatment for patients with aggressive
NHL Stage ME. Although the role of adiuvant radiotherapy in this setting of There Is no consensus on (be optima] treatment for children with large cell anaplaslic
patients is fMMilfd. at the present time this approach maybe considered the standard histology. Wilb this regimen Ibe event free survival was jutt les> than 6 0 1 ' in
therapyforthese pnHf^t cotnparisoa lo that seen for children with malnrc 1) cell lympumna which ii KHT It
remains to be seen whether a hybrid treatment utilising a combination of H cell NIIL and
Ilodgkin'slypc treatment with procarbazine and cblorambocfl will produce better results.
DSV is supported by a fellowship from AIRC
571 572
WHICH TREATMENT IS PREFERABLE FOR ANAPLASTIC LARGE-CELL PRIMARY TREATMENT OF HIGH GRADE NIIL : FINAL
LYMPHOMA-HOOGKIN'S-UKE (ALCL-HL): MACOP-B OR ABVD? ANALYSIS OF A GERMAN MULTICENTER TRIAL
U. Kaiser, H.Koppler, I.Uebelacker, K-Havemann for the German
P.L Zinzani, for the Kalian Cooperative Study Group on Lymphoma. High Grade NHL study group. Zentrum Innere Medizln, Philipps-
Institute of Hematotogy "Seragnotf, University of Botogna, Italy Unlversltat Marburg, 3S033 Marburg, Germany
A randomized multlcenter trial comparing 4 cycles of CIIOEF with
From September 1988 to October 1993, 90 anaplastic large cell lymphoma
4 cycles of two alternating regimens, hCHOP and IVEP followed by
(ALCL) patient* were treated with third-generation chemotherapy regimens
Involved field (IF) radiation with a dose of 35 Gy for both
(F-MACHOP or MACOP-B) during the course of an Italian multicentric
treatment arms was conducted between 1986 and 1990. Included
randomized trial on high-grade non-Hodgkin's lymphomai (HG-NHL). In
were 175 patients with primary high grade (hg) NHL, stages II-
particular, 47 patients had ALCL of the common type (CT) and 43 had
IV. Treatment results after two years have been published (Ann
HodgHn's-like (HL) subtype. Complete remission was achieved in 66/90 Oncol, 1994) and have shown no benefit for the alternating
(73.5%) patients [33/47 (70%) with ALCL-CT and 33/43 (77%) with ALCL- regimen. We performed a final analysis after 5 years. Overall
HL]. The probability of relapse-free survival (RFS), projected at 63 months, survival was not significantly different in both treatment arms :
was 67% for ALCL-CT and 82% for ALCL-HL The data of the present study 58% for both groups combined. In a multivariate analysis pre
confirm that ALCL responds to third-generation chemotherapy regimens treatment LDH was the most valuable prognostic marker followed
slmaarty to other aggressive malignant lymphomas in terms of both CR and by stage. Among the 47 patients who relapsed 42 patients could be
RFS rates. further analyzed: median interval to relapse was 12.5 months (6-
As there is no proof from the literature that ALCL-HL cases actually 63 months). 4596 ( n - 1 9 ) of the patients relapsed exclusively
correspond to HodgkJn's disease (HD) with an unfavourable clinical course, outside of the prior radiation field, 29% (n-12) relapsed Inside and
outside, 19% (n-8) relapsed exclusively Inside the radiation field
and since variances still exist as to the optimal treatment of ALCL-HL we
and 7% (n-3) relapsed with an acute leukemia. Data underline the
have planned an ongoing randomized prospective muWcentric trial for
value of IF radiation therapy. In an ongoing study five cycles of
ALCL-HL, witri the aim of assessing the effectiveness of standard protocols
CHOEP are compared to three cycles of CHOEP followed by high
for HD (ABVD scheme) versus third-generauon chemotherapy regimens
dose chemotherapy and autologous stemm cell support for
(MACOP-B) as complete response (CR) and RFS rates. Since September
patients with high risk hg NHL In both arms IF radiatio is
1994 we have so far randomized 30 ALCL-HL (according to REAL
performed after chemotherapy. Currently 200 patients have been
classification) patients of whom 25 (10 for MACOP-B and 15 for ABVD) are
included demonstrating the feasibility of the study.
currently evaluate for the response rate. The two groups are fuBy
comparable In their main cfinteal features, without any significant difference.
So far, the CR rates have been 80% and 73% in MACOP-B- and ABVD-
treated patients, respectively.
154 9. Aggressive lymphoma
574
CHEMOTHERAPY FOR YOUNG PATIENTS BELOW 60 YEARS TREATMENT OF AGGRESSIVE NON-HODGKIN'S LYMPHOMA WITH A
WITH INTERMEDIATE GRADE (IG) NON-HODGKIN'S PROMACECytaBOM-UKE REGIMEN : IMPACT OP THE DELIVERED
RELATIVE DOSE INTENSITY FOR MITOXANTRONE AND
LYMPHOMA (NHL) USING FOUR DIFFERENT DOXORUBIC1N- CYCLOPHOSPHAM1DE ON THE SURVIVAL.
CONTAINING REGIMENS.
W.Fercmanj, P.Neve, L Marcdis, A Dewowere, M Morret-Rauis, JP Kadtu, H Boodue.
RXiang, D.Todd, Y.L.Kwong, C.S.Chim, C.K.Lcc, F.C.S.Ho*. D Brenez, D Brohee, JL Dtrgent, A Verhest d i m e of Haematology E n t i r e University
Hospital Brunei*; Belgian Lymphoma Group, Belgium.
Departments of Medicine and Pathology*, University of Hong Kong,
Queen Mary Hospital, Hong Kong. MitoxaiUioiie has been incorporated '
nan-Hodg)dn'( rymphoma (NHL) with a comparable efficacy tnd sometime* a tower
Doxonibicin-containing chemotberapeutic regimen, e.g. CHOP, is the todcity. Five j e a n ago, wt started a phase II study with a PROMNCECytabom regimen
corner-stone for treating IG NHL. This study compared the efficacy of 4 in aggrestive NHL. Miuxcantron* was given at 5 mg/m ] instead of 25 mg/m 2 of
doxorubidn; the othen drugs w e n ° - h —V"* according to the SWOG original regimen.
different regimens in a group of young patients below 60 years with IG
PATIENTS: 30 patients were eligible (M-17.F-13X mean age 54.2 y (17-69);
NHL. 405 patients below the age of 60 with IG NHL received four increased LDH and p2 mkroglobulin respectively in 50% and. 23%; 1WF D - 3 . P - 4 .
different doxorubicin containing regimens: 222 (55%) had CHOP, 87 G-14, H - 2 , > 3 , K l - I - 2 , other-2;atrioodal sites present in 73%; International Index
(21%) had BACOP, 72 (18%) had m-BACOD and 24 (6%) had Low (n—1IX Low-Interm. ( n - 9 ) , High-Interm. (n—5). High (n-5).
ProMACE-CytaBOM. There were 44% females and 56% males. The RESULTS: The response rate after 6 cycles was: CR-17 (57%), PR-7 (23%), primary
median age was 48 years. 71% had Stage I disease, 27% Stage II, 18% refractory 4 (13%) and early toxic deaths 2 (7%). The maximal tcoriciry grades (mean
of the highest WHO grade for each patient) were £ 1 except for Hb (1.4) and PMN (2 6)
Stage II and 48% Stage IV. 32% had B symptoms, 18% bulky disease and for the 167 cycles analysed. The DFS (CR patients) reached 66 % at 5 y (mean f-up- 31
48% a extranodal primary. For those who were immunophenotyped, 23% months). For the entire cohort, progression-free survival and overall survival (mean f-
were T-cell and 77% B-cell. Additional local radiotherapy was given to up: 28 months) were respectively o f 5 6 % a a d 55 % m 4 y. These resulu are dowry
43% of the patients following chemotherapy. For patients with Stage I/I! comparable to those of the others previously reported multictturic triali using
disease, 86% had a complete remission (CR) and the 5 year disease free PROMACECytaBOM or PROMACECytaBOM-like regimen*.
DOSE INTENSITY: Patients who had received the 6 cycles and more than SO % of
survival (DFS) was 76% for CR patients. For those with advanced Stage delivered RDI for N and CPM (full-dose cohort) were compared to the others (low-dose
III/IV disease, 57% had CR and the 5 year DFS for CR patients was 37%.
Downloaded from http://annonc.oxfordjournals.org/ by guest on January 2, 2012
cohort) in terms of PFS and OVS. The difference was highly significant in favor of the
There was no significant difference in CR rate, DFS and overall survival full-dew cohort m—«im PFS unreached v» 19.5 months (togrank p - 0.02), median OVS
for the four regimens. Significant independent variables affecting unreached vs 26 months (logrank p - 0.04). The 3y OVS for full-dote vs low-dose was
prognosis on multivariate analysis included clinical stage, B symptom and respectively 74 % vs 42 % (mean f-trp 33 months vs 30 months).
CONCLUSIONS: 1° PROMNCECytaBOM is an effective regimen with a moderate
serum lactate dehydrogenase level. We concluded that the newer
generations of doxorubicin containing regimens did not significantly toxiaty.
2° The use of colony-stimiilating factors is ttwtin to sustain the
improve the clinical outcome of these patients. delivered RDI in selected patients.
576
LONG-TERM FOLLOW-UP STUDY OF A COMPARISON OF CVU5RIAMYQN-0P (CHOP) C H O E P C H E M O T H E R A P Y IN I N T E R M E D I A T E A N D H I G H G R A D E
VS. C-EP1RUBICJN-0P (CEOPL WITH PHASE "B" BLEOMYDN. IN INTERMEDIATE AND NON-HODGKIN LYMPHOMAS
HIEH GRADE NON-HODGKIN'S LYMPHOMAS (NHL).
AOnOrk, E.O.K*ndemir, M.Yaylaci, N.Oskem, Department of Hematology-Oncology,
J. Otai Maquao*. E. Go/da VaW. f. Romafo Qards'. A AtMtf. U.J. Nambo*. JA. CMgado Lama*' OATA Haydarpaja lstanbul-TURKEY
^tdaOncotoglaCMNSiglo>0«.*\«S& Ma»fco Of ond 1>« C*»nto». MSS Guadatajatn. Mtofcn
Thirty-nine intermediate and high grade Non-Hodgkin rymphoma patients were treated
Recant obtatvebon* on rtaiiwt mufti of NHL he*« encourogadrenawadiraareM on O O P and with CHOEP prothocol (Cydophosphamide, 750 mg/m2 1st day, Adriamyrin, 50
CHOP-ik»reglmatAmong CHOP vena**, tw *ub»*Uton o) down*tc«i by 4-apiiubran (CHOP) may mg/m2ls day, Vlncristine, 2 mg 1st day, Etoposide, 100 mg/m2 on days 3-5 and
ha\»*padeiiniponAncac^ttl^tactlTeldo)stngot2Vrn(toxraxatalntaclnnaalwaalaVWan«l>.«MLauciMXinntsoja From July 11M7
year diwiTr free survival was 50 per cent and total survival was 60 per cent
ID Oacarabar 15.1991 3> paMnti ware indudad n a randomiiad way in asoh pnHocol oim. Mnoi
Grade II—III granulocytopenia, thrombocytopenia and grade IV alopecia were the most
\Mnnc*% raoanftig ega. MX liunjiugy and piijgnoJlc loctora ware obHfvad in botfi group*
encountered side effects due to the chemotherapy.
rendaring taut My compa/aUa. Ra«pon*a. madum disaaaa Iraa irtarvol (mOR) and madwn o^«fal
*orvk«l (mOS) ware anolytad accortjaig w(h t» Wamataial Propotaltotproflnottc danitcekon-In
penanttwUihigh 1/2 and high RtK. CHOP provad to b* more atcaoou* wtti a CR ol (3 CV « •
inondi*ofniOF)lotlwtawhoo6tair^CR44*monb*o(mOSenlSu^oldaahpa«ant*.vt oCRol
U.4X.13mona>*of mDH. 11 montw olmOS end SI SX oldaafc* In »ia CHOP group ButinpeMna
wtn low oi low 1/2 ri*k tare ware no tjgnacsnt dftaianca* batwaan Da t arm* « * 17.4/82 JH O\
65./SS- mOH 74>/72« mOS and 2V29.4X of daaha.totCHOP/CEOPretpactvalyThar, ware no
ikjn^coM uHltiaiir**regnrrfngfonciatogic natay b 10
cm) and i III intermediate or high grade (WF) NHL were included in the GOELAMS yet clarified. We refer the results of a cooperative randomized trial between two 12 weeks
07 protocol. This consisted of 4 courses of chemotherapy (ABAB or AAB8 by rr^imfn* ( VACOPB and V1COPB) different only for antracydine drug used
initial randomization). Course A • Epirubicin 100 mg/m2 IV d2, Prednisone 80 (Doxorubicine vs Idarubidne). Tbe purpose of tbe study was to test tbe efficacy and toxichy
mg/m2 (V d1 to d5, Cytoxan 1,2 p/m2 (V d2 and Ekfisine 3mg/m2 IV d2 and d5. of Idarubicine in DLCL.
Course B - Hosfamtde 1,5 g/m2 IV d1 to d3, Mitoxanlrone 10 mg/m2 IV d1-2, Patients and Methods Since June 1991 to December 1994 103 pts with DLCL in
Etoposide 100 mg/m2 IV d1 to d3, and Methotrexate 100 mg/m2 d1. Courses advanced stage, with age l, 31 pts B symptoms, 58 pu LDH level above normal ; 37
prognosis significance on SV and EFS of sex, age (>2) tcoddties occurred in 22 pur 2 cutaneous, 4 mucositis, 3 peripheral neuropathy, 3
hepatotoxicity, 3 infections, 1 diabetis, 2 pulmonary embolism , 1 paeumothorax and I
In univariate analysis (UVA) in the ITT pts the only factors influencing SV were LDH deep venous thrombosis. Mucosal toxidty was significantly lower in pu treated with
Downloaded from http://annonc.oxfordjournals.org/ by guest on January 2, 2012
level (>2N), PS (>1), BM involvement present at diagnosis and ASCT. Stage IV VICOPB (p-0.02). CR was obtained in 79% of pts treated with VACOPB and 56%
without BM involvement at diagnosis was not of adverse prognosis significance.
EFS was affected by the same factors. In a muttivariate analysis (Cox) if ASCT is (Idarubidne 8 mg/sqm ) and 75% (Idarubicine 10 mg/sqm) with VICOP ( p-n.i);
entered in the system only LDH level remain significant for survival and EFS. In prognostic factors that negatively affected CR were: stage IV and BM infiltration for both
ASCT, patients LDH and stage influenced SV in UVA and only LDH level in Cox, schedule. With a median FU of two years tbe OS and DFS were not significantly different
LDH only in Cox influenced EFS. The single factor influencing ASCT feasability between the two treatmem arms: VACOPB ( 73% and 70%) vs VICOP-B ( 56% and 60%
was BM involvement at diagnosis. p-n-s.)
Conclusions are that ASCT may abrogate the adverse effect of BM Involvement, Conclusion: Idarubicine is less toxic then doxorubicine and 10 mg/sqm is easily tolerated ;
high LDH level (>2 N) is the most adverse prognosis factor even for ASCT at 10 mg/sqm its shows the same efficacy of doxorubicine in DLCL, but this prdinunar)
patients. observation must be confirmed by In a larger series of pts.
579 580
ALTERNATING CEOP/CNOP WITH INCREASED DOSAGE OF AfTtsstve Don Hodgldn Lymphoma (NUL)i Experience wttfa the CHOP
ANTRACYCLINES IN INTERMEDIATE-HIGH GRADE NHL regimen In a single Institution.
CMonnent, J.Bauer and SXeyvnz. Centre plundisciplinaire d'Oncotogie,
F. Di Raimondo, G. Milonc, G.A. Palumbo, M. Pafumi, R. Giustolisi
CHUV, 1011 Lausanne, Switzerland.
Institute of Hematology - University of Catania - ITALY
In a recent piN'ori"". Fischer (NEJM 1993) have shown that 3 years survivil
In a previous itudy we have demonstrated that in a CHOP-like scheme (yj) of patients with intennodiate or high grade NHL treated either by
the substitution of Adriamycin in rotation with Epirubicin and standard CHOP chemotherapy or by more intensive regimen is equivalent. In
Mitoxantrone (CEOP/CNOP) does result in a better tolerabilily of other reports, Shipp (JCO 1990) demonstrated that high dose Methotrcxale
therapy with the same response rate as CHOP. In an attempt to increase (HDM) wti not better than low dose Methotrextte in preventing central
the percentage of response in the alternating CEOP/CNOP scheme, we nervous system (CNS) relapses.
We have retrospectively analyzed 129 of 173 patients with aggressive NHL
escalated the dosage of Epirubicin from 50 to 100 mg/m2 and that of
(IWF: E-J) treated in our institution between Juanary 1982 and July 1995 with
Mhoxantrone from 10 to 16 mg/m2, while keeping the standard dosage a standard CHOP (G.I) or CHOP with HDM (G.U). Preliminary results are
of CTX (750 mg/m2), VCR (1.4 mg/m2), and PDN (60 mg/m2). summarized in thi» following table:
Twenty consecutive patients affected by NHL from E to H of WF, were £4 mtmAa SIWIII rv B-IHWHH rsa-i £B a™rw.cn
enrolled in this study. Median age w u 48 ys. Nine patients were at initial OI Jl Hi 41H IMH 17% 67.1% 51%(4I 69%)
stage (I. It) of disease, while eleven were at advanced stage (III, IV). Oil 71 47 49% 11% S7S 11.7% 64%(5I_77%)
1
Complete remission (CR) was significantly better for G 1 (pO.001); however
Hematological toxichy was negligible and no patient required growth
5 yJ was identical in both groups. Moreover, three of the four CNS relapses
factors in order to maintain the 3 wits schedule No cardiac torichy has occur in group G U.
been encountered so far, but four patients experienced grade 3 GI 5 y j and CR were then estimated by grouping patient according to the
toxichy. Fifteen out of twenty patients (75 V.) obtained CR, two patients tnii-nmim.l Pronostic Index (Id) (NEJM, 1993) - PS; LDH levd;ige; stage;
(10 %) PR and three (15 %) showed progression of disease. When we extranodal /titM«*., Only 85 patients met these criteria :
examined our patients according to the International Prognostic Index in a in in
we found that CR was achieved in all the patients with low risk and in 3 L 31 SO% 17% 74%
U 15 72% M% U%
out of 5 in the low-intermediate category, but in none of the patients m 13 61% 55% 4J%
affected by high risk NHL. H 1 IP1 is comparable to the original results.
seem useful in high risk patients and may induce more cxtra- However, due to small number of patients and large confidence mtervill, it
bematological toxichy. does not reach statistical significance.
156 9. Aggressive lymphoma
ITALIAN NON HODGKIN'S LYMPHOMA COOPERATIVE STUDY GROUP Lymphoma of Burkitt and Burldtt-like type is curable with intense short-
(NHLCSG): PRELIMINARY RESULTS OF RECENT TRIALS FOR term chemotherapy.
DIFFUSE AGGRESSIVE NHL A Johnson, J Ltndenxh & E Cavtllin-Stihl. DcjX of Oncology, Univ Hosp or Lund, Sweden.
T.Crrisesi*. G.Santinl . PXeoni, AJorceuini, P.Coter, L.Salvagno, RXenturioni, Burkitt and Burkltt-like B-ceil lymphoma (BBL) is a rare (1%) but important lymphoma
MJtSertoli, C.Guarnaccia, L.Tedesdu, MCongju, M Vespignani* and VJtazoli subgroup to be recognized in young adults wilh rapidly progressive disease. Gross abdominal
•Department of Hematology, SS.Oiovarmi e Paolo Hospital, Venice, Italy tumour with ovarian or gut involvement and ascites is common. A large tumour burden and
high proliferation rate enhance the risk of the tumour lysis syndrome.
In 1992 the NHLCSO published the remit! of conventional chemotherapy (CCT) and Since 1985 we have treated all BBL patients under 40 yean of age wilh a short alternating
ABMT for offtniive NHL. The condusioni we drew were: a) second and third 3-month schedule according to the German NHL -BFM protocol 1986 and 1990. In recent
generation regimeni do not improve DFS and PFS, b) the role of ABMT in 1 CR wa« years support with G-CSF has made it possible to treat patients 40-50 years old.
Patients. Between 1985 and 1995, twelve patients, (10 males, 2 females, age 17 -50 years,
uncertain and randomized itudiet were required.
median 22) were diagnosed with BBL. The major presenting she was abdominal with bulky
Therefore we Parted 8 new trial in which a tenet of consecutive patients was divided
tumour or peritoneal spread (7) and ascites (3). Other sites w e n lung/mediastinum ( I ) and
in 3 groups according to age, Mage and negative prognostic factors at diagnosis.
extradural with medullary cord compression (I). Bone marrow involvement was present in
Up to June 1995, 206 new patient* (groupi F-O-H-K-/WF), wilh an age 15-59 yean only two and concomitant CNS involvement in one. N o patient was leukaemic. One patient
entered 3 different triali. An interim analyst ii presented. was stage I (cervkal node), two stage II (tonsil, sinus) and 9 stage IV. Three patients were
STUDY A: The objective wai to evaluate the impact of conventional CT on patienu severely ill • one moribund with ascites and pleiiral effusion, one uremtc and one
with low tumor burden. 41 patienu in stage II and III without advene prognostic paimpamic. LD was > 3 x normal value in 5 patients.
facton were treated with VACOP-B regimen- Three-year actuarial curvet thow a OS, Treatment Increased diuresis, alkalinUation and prednisone 30mg/m 1 d 1-7,
DFS and PFS of 81%, 77% and 73% respectively. cyclophosphamkJe (Ox) 200mg/m I (with menu) d 2-6 and methotrexate 12mg h d I.
STUDY B: The endpoint wai to evaluate the effectivenets of high dose Alternating Block I Dexatnethasone(Dxm)10mg/m J dl-7, C o 2 0 0 ™ ^ ' d 2 - 6 ,
chemotherapy (HDT) in increasing OS and DFS. 124 patienu in stage II-IV with one methotrexate (Mtx) MXhng/m1 23h infusion d 2 (leucovorin 30mg x 2 4!h and 54h after
or more adverse prognostic factors were randomly allocated to receive either start), Mtx 12 mg it d 2, tentposide \6$mgjm'd 6, cytarablne 300 mg/m 1 d 6 . After one week
rest alternating block II Dxm, Ctx, M a , Mtx it as in block I, doxombicin SOmg/m1 inf 2 h d
VACOP-B or VACOP-B+ABMT. Actuarial survival (67% in both arms) and DFS
6. Block I and II were repeated three times followed by CNS irradiation 24 Gy (not stage I).
(56% vs. 65%) curves at 3 years are similar, showing no advantage in adding HDT.
The present protocol NHL-BFM 1990 b augmented by Inclusion of Ifosfamide instead of
STUDY C: 41 patients in stage IV with bone marrow involvement were treated wilh
Ctx In one block and treatment further differentiated according to risk group. CNS irradiation
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VACOP-B until maximnm response followed by high dose CY+d/QM-CSF. is omitted and it profylaxis given with triple drug combination (Mtx 12rag, Cytanbine 30tng,
Peripheral progenitor cell rescue was given after Mebphalan+TBI. An interim analysis Prednisone lOmg d I in each block).
shows three-year OS and DFS curves of 67% and 49% respectively. Results. All patients obtained complete remission and remained disease free during a median
These preliminary retuhi allow us to draw some conclusions: 1) in the favorable follow up of 48 months (3 • 120) and normal physiologic function was restored in all.
group of patienu, the impact of conventional CT is reasonably satisfactory. 2) In Discussion. Standard chemotherapy for high grade lymphoma has produced poor results in
group B the intensification with HDT and ABMT teems not worthwhile, wilh no BBL and high dose therapy with stem cell support has been advocated. It is our experience
advantage in OS and DFS. For this group of patients a new approach with a different that BBL is cured in young adults with the use of short term intensive chemotherapy as has
rationale is needed. 3) Study C indicates that HDT has a good impact in patienu wilh been described in childhood BBL. The rapid clinical, pathological and immunological
BM involvement, independently from other prognostic factors recognition of this entity is decisive for the outcome.
E3CALATED DOSE EP1RUBIC1N (epi) - CYCLOPHOSPHAMIDE (cyclo) WITH COMPARISON OF THE ABILITY OF GM-CSF AND O-CSF TO
FILGRASTtM FOR PATIENTS (ptt) WITH AGGRESSIVE NON-HOOGKIN'S AMELIORATE TOXICITY FROM AN INTENSIVE TREATMENT
LYMPHOMA (NHL). PROTOCOL FOR NON-HODOKIN'S LYMPHOMAS. Adde M, Venzon
D, Horak I, Shad A, Arndt C, Gootenberg J, Seibel N,
A. Grigg, M. Wolf, J. Levi, J. Bartlett, M. Green. Royal Melbourne Hospital, Neely J, Nieder M, Owen H and Magrath I. National
Peter M i c C a l u m Cancer Institute & Royal North Shore Hospital, AustrsBa. Cancer Institute, USA.
Based on a phase I dose-escalation study of ept-cyclo with fUgrastlm support
In pts wSh solid tumours, a mutU centre phase II study in NHL was Initiated In We have treated 64 high risk patients with either SNCC
1963 using the maximal dose found to be deliverable over multiple (46) or LC (18) lymphoma with a chemotherapy protocol
treatment cycles. Epi was used Instead of doxoruWdn as i t equlmolar closes consisting of two regimens, A and B. Regimen A
It is less cardlotoxtc and less myelotoxic, allowing dose-escalation. Pts included CTX, ADR, VCR, and high dose MTX, and regimen
received IV epi 150 malm', cyclo 1500 mg/m 1 , vtneristine 2 mg on day 1 B: IFOS, VP16, and high dose ara-C. Two alternating
and oral prednlsolone 100 mg for 5 days, together with daily flkjrasilm 5 cycles of each regimen were given and all patients
ug/xg SC from d1 until W B O 1 0 x 1 0 / 1 Cycles were given at 21 day received IT ara-C and MTX. Patients enrolled on the
intervals. Twenty-two pis have been treated, with • median age of 44.5 (20- study through December, 1993 were randomized to receive
70) years. The underlying disease has been de novo Intermediate grade or GM-CSF (23) or no CSF (20). In randomized patients,
tmmunoblastlc NHL In the majority (18 pts); of these 39% had B symptoms,
GM-CSF administration began on day 13 in A cycles and
44% h i d elevated LOH, and IB had either stage 2-4. extranodal or bulky
disease. The regimen has been reasonably tolerated with febrile neulropenli day 7 in B cycles. EFS for patients enrolled through
(FN) the major toxtcly. occurring In 13/22 (59%) of first cycles but only 12/91 December, 1993 was 92%. A comparative analysis did not
(13%) of cycles 2-4. Tfw neutrophfl nadir occurred tattler and was longer In show statistically significant differences in duration
cycle 1 vs later cycles. Only 9 of 91 (10%) cycles 2-6 have been dose of neutropenia or the incidence of fever or infection
modified due to prolonged neulropenli (n«2) or platelets 1 year post
patients according to the administration schedule for
treatment have recovered their fertility; one woman b pregnant. One m a l e
remains azoospermtc at 13 months. Seventeen of me de novo pts are GM-CSF. Toxicity data from 19 G-CSF treated patients
evaluibte for response (1 too early). All 14 who achieved CR i r e currently was compared with the GM-CSF and control groups. In
•Bve In remission, with a median foflow-up of 23 (4-33) mths from diagnosis. regimen A cycles, the duration of neutropenia was not
The other 3 de novo pts filled to achieve CR and died of disease. These different among the three groups. However, the
promising preliminary results have led to the Initiation of a randomised study duration of neutropenia was shortened in B cycles for
In Intermediate grade NHL comparing this regimen with 'conventlonaC dose GCSF treated patients (median, 5 days compared to 10
(epi 75 mg/m 2 , cyclo 750 mg/rrr) treatment. days for both GM-CSF and control groups) . Although the
duration of neutropenia was shortened by G-CSF,
platelet recovery prevented earlier initiation of
subsequent chemotherapy cycles and higher dose
intensity. Patients in B cycles, however benefited
from the shorter duration of neutropenia.
9. Aggressive lymphoma 157
585 586
INFLUENCE OF G-CSF ON THE NEUTROPIDL RECOVERY THE PATTERN OF FIRST RELAPSE IN PATIENTS WITH
HISTOLOGICALLY AGGRESSIVE NON-HODGKIN'S
IN HIGH GRADE NON-HODGKIN LYMPHOMAS LYMPHOMA, PREVIOUSLY TREATED WITH ADRIAMYCIN-
CONTAINING COMBINATIONS
Gy. Varga. Z. Borbenyi, K. Piukovics, I. Marton
2nd. Dept. of Int. Mcd. Szcnt-GyOrgyi A. Med. Sch. Szeged. Hungary N. Hajm, A. Talmor, M. Ben-Shahar, M. Leviov, R. Epdbaum.
Granulocyte colony-stimulating factor (G-CSF) reduces the degree Department of Oncology, Rambam Medical Center and Technion - Israel
and duration of neutropenia in patients with high grade non-Hodgkin Institute of Technology. POB 9602, Haifa 31096, Israel
lymphoma after chemotherapy. The purpose of this study was to
determine the effect of G-CSF on the leukocyte recovery in patients The pattern of fint relapse was retrospectively analyzed in 71 patients
with high grade non-Hodgkin lymphoma. One group of the patients [pts] with histologically aggressive non-Hodgkin's lymphoma who had
received G-CSF (Neupogeo s u«/Vg) in 25 cycles of ProMace-MOPP been treated previously with adriamydn-containing chemotherapy,
on days 9-14 and in 32 cycles on days 18-27. The leukocyte count with/without radiotherapy. Relapse was limited to previously involved
increased from 6.8 ± 22xG/l to 14,4 ± 6.8xG/l in 96% of the
patients within 2-6 days. After day 14 of the cycle (Lv. Methotrexate) [old] sites in 11 [15%] pts only and to previously uninvotved [new] sites
the leukocyte count dropped to 32 ± \2xG/\ and G-CSF raised it in 22 [31%] pts. In 38 [54%] pts, relapse occurred in both old and new
to 15,7 ± 6,6xG/l within 2-6 days in 87% of the cycles. In a sites. In none of the pts was the relapse limited to a site of prior bulky
second group of patients Neupogen was given only in febrile disease. For the following analysis, bulky sites and sites that underwent
ncutropenic states during 21 cycles. The febrile neutropenia occurcd surgery or radiotherapy were excluded. Relapses in new sites were more
8 + 6.5 days after the cytostatic treatment. One part of patients frequent among extranodal [EN] than among nodal sites. Of 47 EN sites
received first line therapy, others were heavily pretreated. In both at the time of recurrence, 41 [87%] were new she*, compared to 99/178
group the initial WBC count was 1,0 + O^xG/1. In the former group [56%] nodal sites [p
were treated with atogeneic BMT. AS patients responded to ASHAP (13 CR, 3 PR). PMItCEBO was given for a total of two weeks (3 patterns) four weeks (3 patients) six
With a median follow-up of 24 months al CR pts except 1 have remained alive in weeks (2 patients) dgbt weeks (9 patients) and twelve weeks (2 patienu). Overall
remission, while the 3 PR pts have progressed and died. Sixty-four pts received response rate was 14 cat of 19 (74%) with 7 patients achieving complete clinical
ASHAP as a salvage regimen to be foBowed with HOC and APBSCT or ABMT for remission. Median duration of response was twelve months (1-27 months), actuarial
those responding pts under age 66. Their median age was 53 years (range 17-SO). mean survival from relapse was seven months with DO difference between histologtcal
The larger histologic subgroup was intermediate grade lymphoma Twenty-four had types. Two patienu died from mddental cardiac disease. There were ten episodes of
never attained a prior CR. A total of 52 (81%) pts responded (29 [45%] CRs. 23 neutropeula (total nentrophll coont less than 1.0) with three episodes of neuiropenic
(38%) PRs) and 34 of these pts received HDC for consolidation With a median sepsis. This hvltxirt one patient with bone marrow failure doe to diffuse Infiltration at
follow-up of 33 months, overall survival was 52% at 56 months Time to treatment relapse. In l-8%; elevated LDH=47%; stage III-IV-41%; tumor>IOcm-28%;
ranged between 16 and 78 (mean 42.5). They received 1-6 MICMA courses (median 3). Eleven extranodal site>l-21%; bone marrow involvcment=l3%.
achieved the CR, 18 a PR (reduction of rymphoma > 50%), 14 were NR. One patient is still
unvaluable. 38 patienu received G-CSF 5 ug/kg torecruitperipheral blood stem cells or in case The MAMI protocol (2 cycles every 21-2Sd) consisted in Mitoguazonc (400 mg/m2
of severe neutropenia (llll"#l of non cross rcsutant drugs, ind
only few other drugs can offer therapeutic chances for the NR p"i"«« Our MICMA regimen pts are surviving more than 2 yean after salvage treatment. Adverse prognostic
constsu of chemotherapeutic agems not administered before or employed with a different factors for survival at the time of MAMI for all pts were: refractory disease
schedule. The MICMA Is well tolerated overall if associated to the G-CSF, that allows also the (p 10cm (pO.OOl), and elevated LDH (p7S% reduction) (1 proceeded to BMT), 2
a PR and 3 showed no response. Median folow up I* 30 months (range 3-45), and
resistant HD in our small group of such pts.
6 lurvtve In CR, 3, 12, 16, 2 0 , 33 and 38 post chemo.
We beSevt thl* to be a promising treatment for difficult HD and toxidty ha* been
160 9. Aggressive lymphoma
597 598
PHASE II TRIAL OF VINORELBINE (VNB) IN PATIENTS WITH Vlnorelbine (Navelbine) as salvage therapy in heavily pre-treated patients
REFRACTORY LYMPHOMAS. with Hodgkln's and non-Hodgkln's Lymphoma.
V. Churion Sileni', A. Bononi', M. Rupolo1, F. Gaion', L. Sah/agno1, S.M.L. S Rule, M Tlghe, S Johnson, Department of Haematology, Taunton and
Aversa', M. Sorarii', M.V. Fiorentino'. Departments of Medical Oncology,
Somerset Hospital, Musgrove Park, Taunton, Somerset, UK
Hospitals of:' Podova, ' Rovlgo, ' Camposamptero; Italy
The purpose of this phase II study was to evaluate the activity and the toxicity of Thirteen heavily pre-treated patients with relapsed Hodgkin's disease (6
VNB tartrate (a novel semisintetic vinca alkaloid) in pts withrefractorylympbomas. patients) and high or intermediate grade non-Hodgkin's Lymphoma (7
Patients and Methods: From 1993, 17 patierts (pts) were enrolled. VNB wai patients) were treated with the semi-synthetic vinca-alkaloid Navelbine as
administered as a single agent (without steroids) at die dose of 30 mg/Tn'/wk i.v., in single agent salvage therapy. The median age of the patient group was 47
250 ml 0.9 % sodium chloridrc and infused in 30-43 min. Treatment was continued (range 24 to 78 years). The median number of prior treatment schedules was
until progression of disease. Median age was 67.5 (range 17 to 87), 4 pts were males 2 (range 1 to 8) of which 6 patients had had a prior autograft procedure and
and 13 females; median PS was 60 (40-100). Four patients had low grade rymphoma, one patient a prior allogeneic bone marrow transplant. At treatment with
11 had intermediate or high grade and 2 had Hodgldn'i disease 5 pts had B Navelbine, the stage of disease was as follows: 7 patients stage IV, 2 stage
symptoms and 7 had bulky disease. Extranoda) involvement was present in 5 pts and HI, 3 stage II and one stage I. Navelbine was given at 25 mg/m2 IV on days
bone marrow (BM) infiltration in 2. The median number of prior chemotherapy 1 and 8, each course repeated every 21 days. The median treatment cycles
regimens was 2 (range 1-5); prior radiotherapy in 5 (31%). 2 pts underwent also
received was 3 (range 1 - 9). The dose of Navelbine was reduced in 4
ABMT and 5 Interferon. A total of 125 cycles of VNB were administered.
Results: 16 pts are evatuable. Seven pts (44%)responded:complete remission (CR) m
patients due to neutropenia and treatment delayed in 5 patients following
2, partial remission in 5; stable disease in 7 (44%). One completerespondcrunderwent infectious complications,in 2 patients febrile neutropenia, one pneumonia and
ABMT and is in continuous CR (7+ mo.) The median response duration was 3 mo one shingles. The only other side effects were severe phlebitis and
(range: 1-5). The major dose-limiting toxicity was hacmatologic. Dose reductions were constipation seen in one patient. There was little nausea or vomiting and no
necessary in 5 pts (31%). A delay (median duration: 1 wk) was required in 12 pts (48 alopecia seen.
cycles, 38%). G3 neutropenia occurcd in 3 pts, G3 anemia in 2 pts; thrombocytopenia
was only mild. Non-hacrnatologic toxicity: G3 constipation in 1 pt, G3 fever in 1 pt,
Of the 13 patients, 6 progressed on treatment, one had stable disease for 4
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G3 nausea and vomiting in 1, G2 alopecia in 1. Five episodes of chemical phlebitis
occured. No severe peripheral ncurotoxicity was observed.
months, 5 achieved partial remission of median duration of 9 weeks (3 weeks
Three pts, who started VNB with platelets (ph) . had CNS chemotherapy In this patients was COP-BLAM, CHOP-based, Dexa-
progression after four cycles. No toxic death occurred. Grade 4 neutropenia and Ihrombo- BEAM, A-SHAP, EDAP, Chtorambucil + Predniso)one(Chl+Pred). The
cytopenia occurred in 50% and 6% of administered cycles, respectively Median absolute results of treatment Oex areCR-2, PR-3, partial fesponse-5, no
neutrophil and platelet counts at nadir were 500/uL (range:100-1,300) and I27,0UVUL
response-1, progression-1. Overal 3-years survivals after AutoBMT
(range: 19,000-183,000), respectively. The nemrophil nadir usually occurred between day 9
and 12. AU patients whh grade 4 neutropenia at nadir rccovcicd lo>300/uL ANC within 2-3 and/or PBSCT are 55% in HD, 47% in NHL
days. No transfusional support was required.CKhcr side effects were grade i-2 anemia (46% of Dex treatment Is effective modality for resistant/relapsed
cycles), grade 1-2 mucontis (36%), grade 1-2 infection in absence of neutropenia (15%) and low/Intermediate malignancies. It should used as a nontoxic therapy in
grade 2-3 SGOT/GPT increase (4%). One paiient suffered from grade 3 febrile neutropenic elder patients or as preface for further intensificationn including HSCT.
pneumonia. Hematologic toxicity never persisted at the ume of recycling. Delays or dose
HSCT in patients suffering of high grade lymphomas or HD is
reductions were needed only in seven (14%) cycles, due to earahemaological causes.
Conctashns. The CEVOP-B program whh E and V given as Cl is feasible, wdl tolerated and effective If transplantation has done in CR or PR.
sufBcicnuy active. The study is ongoing.
9. Aggressive lymphoma 161
601 602
TREATMENT OF RELAPSED AND RESISTANT LYMPHOMA WITH UPOSOMAL ANTHRACYCUNES: FEATURES ENSURING A FUTURE ROLE IN
LIPOSOMAL DAUNORUBICIN (DAONOXOMB™, NEXSTAR) THE TREATMENT OF LYMPHOMAS
F.M Muoola and P. GDI, USC - Norria Cancer Center. Lot Angeles. CA 9 0 0 3 3
D.S.Richardson'. M.Tighe'.S.AJohnfon'.S.M.Kdiey'.A C.NevHand1
Departments of Haematology, Royal London Hospital1, London, El IBB, UK DaunoXome and Doxil have recently become available for trsatmint of
&. Taunton and Somerset Hospital2, Taunton, TA1 5DA, UK. AlDS-related Kaposl's Sarcoma. Their toxicotogic and pharmacologic
properties have b m n defined (1,2), but the spectrum of antltumor activity it
16 patients with relapsed or resistant lymphoma (14 with NHL, 2 with HD) only recently being explored. Phase II studies in malignant lymphoma a t
were treated with liposoma) daunorubicin between September 1993 and single agents are ongoing with both DaunoXoma and Doxil. DaunoXom* a t
November 1995. Patients were heavily pre-treated (mean number of regimem weB a t Doxil may selectively be taken up by tumor tissue. Both have
- 3.6,range 1-8). 6 had received high dose chemotherapy with ABMT/PBSCT attenuated subjective toxictties and lesser propensity to cirdiotoxichty.
and one, a sibling allogeneic transplant. 9 patients received 1-4 cydes and one We have found DoxJ active against ovarian cancer with
myeJosuppreuion occurring exceptionally (confined to patients who have
patient 24 cydes at a dose schedule of 40mg/mJ q 14days No patient in this
had total abdominal radiation or prior mhomycin therapy.) Experience in 4
group achieved an objective response; 7 have died (5 from disease) and 3
patients with radiation during Doxfl treatment indicant treatment Is tolerated
remain alive, 2 with progressive disease at S months, one has proceeded to
without undue skin toxidty. Phase I study of Doxil with paclitaxel it
PBSCT and is in dinical CR at 4 months post transplant. The patient who ongoing. DaunoXoma and Doxil may contribute to future treatment of
received 24 cydes of treatment, remains alive and achieved excellent rdief maBgnant lymphoma: selective localization, no dose Bmrting
from bone pain which had been refractory to previous therapy. 6 patients myelosuppresskxi, and tolerance with radiation are among the attractive
received 1-3 cydes at 120mg/m2 q 21 days; one patient achieved a short CR features to be explored.
(4 weeks) and another a partial response after cyde I and is currently Doxfl and DaunoXome have been studied most extensively in AIDS-
receiving further treatment. A further patient achieved a minor response related KS. Both agents are weD tolerated with reduced frequency of heir
(duration 4 months from start of therapy) although cydophospharrude was loss, mucositis. Accumulative doses of 1,000-15,000 m g / m 1 of
also administered for PBSCH during this period. 3 patients did not respond DaunoXome In nearly 2 0 patients have not shown any evidence of cardiac
and 4 have died from their disease Toxiaty, judged according to WHO disease cfinlcally or by repeated echocardiography. Doxil hat also been
criteria, was predominantly haematological and dose dependent, with grade 4 shown to be safe but the cumulative doses in excess of 6 0 0 m g / m 1 have
Downloaded from http://annonc.oxfordjournals.org/ by guest on January 2, 2012
only been reached in a smaD number of the cases thus far. DaunoXome hi a
neutropenia or thrombocytopenia affecting 8 patients (SOS). Infection was
phase III trial was found to be at effective a t a combination of doxorubicin,
common, affecting 10 patients, although in all but 2, episodes were estimated
Adriamydn, Weomycin and vincristint and thus w a t recommended for
to be grade 2 or less in severity. Non-haematological toxiaty was mild, in
approval at first line treatment for KS. Doxil h a t been approved for use in
particular, no patient in the higher dose group snowed any deterioration in AIDS-KS as second line therapy after failure of other chemotherapeutlc
cardiac function. Liposoma] daunorubicin at 120mg/m2 appears to have some agents.
activity against refractory lymphoma and toxiaty is acceptable. We suggest
that further studies with this agent are required 1. GB PS et at.. JCJin QnscJ 13(41:996-1003, 1 9 9 5 .
2. Uziely B et al J CJin Qn£oj 13(7): 1 7 7 7 - 1 7 8 5 , 1 9 9 5 .
603 604
RANDOMIZED PHASE III STUDY O F INTERLEUKIN-3 (rhlL-3) AS ADJUVANT When a malignant lymphoma patient is "elderly"?
T O IEV-CHEMOTHERAPY FOR RELAPSING AGGRESSIVE LYMPHOMAS:
H.H.Gerhartz, F.Mandelll, T.Phllip, S.Tura, R.Helru:, R-Greil, H.J.Sem, C-Huber. Busetto M', Sarvagno L 2 , Guglielmi R B \ Giuslo M \ Coghetto F 5 , Bononi A 6 , Mandolin
W.BJau. LFarber, I.SkJenar, U.Haus, KDnikum Kalkweg, Med. Dep. 47O55 G 7 , Radio E 1 , Anloncllo M 1 , Endrted L», Rosa Bun A 1 0 , Manenlc P " . Fcrraoi E*,
Dulsburg. Puccctli C , Balli M 3 , Zoral PL 5 , Polico C 7 , Bassan F 1 0 , Fiorentino MV 2 and Puii GB1
Patients (pts.) relapsing with aggressive lymphoma loUowIng intensive
combination chemotherapy ( c t x ) usually have a poor prognosis due to tumor
resistance and a bad hematopoietlc reserve. In a imitlcenler trial 179 pts. (48
with HodgWrfs disease (HD) and 131 with non-Hodgktrfs lymphoma (NHL) were
treated with the IEV regimen (Ifosfamtde 2,5 g / m 2 l.v. day 1-3, Epirubictne 100
m g / m 2 l.v. day 1 , Etooostd 150 m g / m 2 Lv. day 1-3) followed by either IL-3 (10 Non Hodgkin'i rymphomas are stcadry increasing among people aged 60 and more, and
pg/kg body weight) or placebo s.c. day 4-15. Seventy-five (42 %) pts. were in first everybody knows (hat elderly people has a reduced tolerance lo oncologic treatments. Bm
relapse, 56 (32 % ) were primary progressive and 48 (27 %) had their second or when a patient may be defined 'old'7 There b not a umvocal definition Age is a continuous
subsequent relapse. The mean age was 53 years, 118 were male, 61 female. quantity, without steps, nevertheless we need a coJpoirt after which the chemotherapy
Beside one or more ctx. regimen 27 % had also previously received radiotherapy scheme should be less besny and dosa of cbemotberapy should be reduced to rvxrid an
One hundred and seventy nine pts. entered cyde 1, 143 pts. received a 2nd e n c s s of toxidty. Time ago the cutpoim was around 60 >t)L; 50-39 (I63JJ); 60-69 (243,32); 70-79 (191,13), 80 and over
groups CR rates were 37 % lor 1st relapse, and 18 % for 2nd or subsequent (71,5).
relapse or for primary progression. The number of Infections and transfusiora as As n-c expected, a highly significant difference in tun-hil among NHL and HD patients
well as the response rates were not significantly influenced by treatment with IL-3 was found (both pO.OOOl). The plotted actuarial J-j-ean OTCTIM mr\ rval probabilm- (5-ATI
versus placebo, Indicating that IL-3 Is Ineffective in the setting of Intensive rescue OS) and hi SE remain stable from the younger age interval (10-19) and s u m worsening
around SOies, with a sleeper decrease for NHL. For NHL the 5-\TI OS % ij 75 0 (± 15.81) at
chemotherapy: Survival probatility at 1 year was 55 % for NHL and 70 % for HD .
10-19 y n , 67.77 (± 7.05) at 30-39 j-rs, 78.47 (± 4 13) al 50-59 'yn, 48 03 (± 4 64) at 6U-69,
Conclusion: IEV chemotherapie proved to be a very effective and tolerable
38.0 (± 5.17) it 70-79 y n and 30.71 (± 9.0) m-er. F o r H D t h e 5 - > n O S % i s 92.59 (± 5 0)
treatment In both relapsing and primary progressive lymphomas. The Insufficient
at 10-19, 92.94 (± 3.65) at 30-39 yn, 83.86 (± 9.46) at 50-59 yrs. 73.95 (± 13 85) at 60-69
dinical effects of IL-3 alone might be overcome by continued application together y n , 67.31 (± 13.62) at 70-79 y n and 31.65 (± 18.19) over. Further anahscs are needed, but
with G-CSF or GM-CSF. these results should be considered in therapy planning.
162 9. Aggressive lymphoma
PROGNOSTIC FACTORS FOR MALICNANT LYMPHOMAS OF THE ELDERLY. PROGNOSIS OF ALL PATIENTS AGED 70 YEARS A N D OVER WITH
A REPORT OF THE 'GRUPPO V E N E T O LlNFOMl'. INTERMEDIATE OR HIGH GRADE NON-HODGKIN ' S LYMPHOMA
Busetlo M*. Ciusto M", Bononi AM, Police R \ Ruppolo M°,Endri«i LA, Gaton F+. R o n D I A G N O S E D BETWEEN 1988 A N D 1992 IN NOTTINGHAMSHIRE
Bias Afii, Maneole P+. Fcrrazzi E#, Puccetli C , B a t o n F(S\ Avcrsa S*, Pizri GB*
RM.BesseIL AJ.Motoney. JJlOcher. J.Tbomlcy,
•Dtrkkn. * laSoKnpb t O u h f a - U o m (VE); TXvUoo. d Ouu-t^i. r«luv»: . D n « ,
C«idn«neo « Oaafafi^b—ao (VI); >D>vn, Department of Clinical Oncology. Nottingham City Hospital N H S Trust,
United Kingdom
Malignant non-Hodgkin ryrrrphomas are becoming more and more Crcqueni world-wide, A uniform treatment policy was used for elderly patients ( > 7 0 years) with
especially among elderly. The Vcnclo region teems to be al first places in Ilflly Tor morulit)'
intermediate and high grade non-Hodgkin ' s lympboma. During the period
sad In"^"™ Since 1991 a rympboraa surveillance project, the 'Rcgutro Veneto LrnfamP.
was established among some oncologic centers of this Region. Data from this register are 1988-1992 3 0 7 palienu were diagnosed in Nottinghamshire (served population
I.I million) as having intermediate and high grade non-Hodgkin i lymphoma.
On September, 1995 there were 1029 registered cases of malignant lymphoma, 509 of 120 of these patients were aged 70 years and over al diagnosis. 12 patients with
whom aged 60 or older. These latter were included in this study. Four hundred! and sixty- non-bulky ( 'cUne-containuig
chemothcrapaJtic combination for the treatment o f elderly patients with
In the U s yean Kvenl reporu regirdal the tratmeat of NHL in elderly Since 1989 in our hiitologicaily aggressive NHL was evaluated. Between January 1988 to november
Division vrc utilized • protocol ipecifkalry denied for elderly puienU (65 y o n or older), MiCEP 1992, fift>-one previously untreated elderly patients (median age : 79 years : range
protocol »tjch w u utilized for the tratment of intermediate or hifb-frade NHL. We have recemery
70 to 90) stage III (19 patients) or IV (31 patients) intermediate or high-grade
reporud nUeroting untie imtinitioc results mint MiCEP protocol (Leukemii md Lymphnmi.
N H L were treated. All patients received cydophosphamide 750 mg/m' IV day I,
1995). We report now Ibe renhi of a nmrlnmirrd tral (MiCEP n P-VABEC) in • mihimito-
vtndesine 3 mg/m 2 IV day I and prednisolone 5 0 mg/rrr1 orally day 1 to day 5
study. Tbe centers were Haematotogy Depoiement of Florence and penfene Diviskns of General
(CEP regimen), every 14 days for 6 months. Patients were classified according to
Medicme.
the risk group defined by the international index as low intermediate (14 patients),
Dct^mi jane 1993 >nd december 1995 54 rl^i^nl" over 65 yean were randomized: 28 entered
MiCEP (Mitonmtrone, Ciclopbupharaidc, VPI6, Predabcoe) arm (A) and 26 entered P-VABEC high intermediate (16 patients) and high risk group (21 patients). Among the 51
(Prebisone, Vincristin, Adnamkin, Blroiririn. VP16, Cictopbosphimide) inn (B). The eligibility patients, 17 achieved a complete remission and 9 had a partial response, with a
requtremenu were F.O.H tuttotype according to Wortinf Formulation, P^. o now only
Age Is an Important prognostic parameter, especially In patients with anecdotic*! report* war* tvalatot* in th* currant Utrature aa to th* natural history and
treatment resuts of tiddly pt* affected by Bl_ Between 1988 and 1955, more than 1000
advanced high-grade non-Hodgkin's lymphoma (HG-NHL) who require more ca**a of non-Hodgkin's lymphoma* among adult HIV-ntgative pU ware ob*«rv*d at our
Intensive therapy. W e Investigated the potential of G-CSF for reducing Institution. BL wa* Diagnosed In 30 u u t and among them 11 pt* (36.6%) wtre older than
myetotoxicity, which Is the most important dose-limiting factor for 60 yrs (median ag* 68 yra; rang* 60-84 yr»). CMcal leaturt* at diagnosis wtre a* follow*:
chemotherapy. Between March 1993 and June 1995, 158 previously mate/lemal* ratio 6/S; stagkx) according to NCI paSotric branch: AR-B (1-5), C O (2-3);
untreated patienu 60 years and older with HG-NHL were included in a staging according to Ann Arbor II (2 pt*), IV (9 pts); B symptom*: 3/11: bufcy dl**aa*: 6/11;
ejUiamxIal diMa**: 8/11 (abdominal organ*, 6 pt»; (kin, 1 pt; t*stid*, 1 pt); bon* marrow
cooperative randomized comparative trial and treated with a combination
Involvement: 4/1 1; CNS Invotvemenl: 0/11; lncrea**d wrum LDH level* (> 500 LM.): 7/11;
therapy including cyclophosphamide, mitoxantrone, vfneristine, etoposkJe, reduced absosrla CD4+ T-cel court* (n(CR) wa* achieved In 8 out of 11 pt* (73%), wilh
response (CR) In 59%: 60% In the VNCOP-B plus G-CSF group, and 58% in a madlan CR duration of 35.5' month* (rang* 3*-91 •). Four pt* ar* maim lining a comlnuou*
the VNCOP group. At 30 months (median 24 months), 68% of all CRs were CR by longtr than 64 month*. Median overal survival lor th* whol* group of 11 pt* wa* of
alive without disease In the G-CSF group and 65% in the control group. 15 month* (ranga 1 -91 •), whfl* nwtSan survival ofpt* achieving CR wa* of 37* monlh* (rang*
Neutropenia occurred In 18/77 (23%) of the G-CSF treated patients and In 6*-91•). Tht 3 non-CR pt* (1 PR and 2 ptogreulons) dbplayed an overafl *urvlval of 11
40772 (55.5%) of the controls (P*= 0.00005). Clinically relevant infections month* (ranga 1-15). No Uwnpy-rdaled toxic death* were obttrved In tha whol* group of
pt*. Intertttlngly, txlranodal tltau** (In particular tkki) repr*«*nl*d th* u*u*l *ttt* o) both
occurred In 4/77 (5%) of the G-CSF group and In 15/72 (21%) of the
(fit**** progrenion and relap**. Our data IndkMle that b I* pottM* to obtain a CR in an
controls (P= 0.004). The delivered dose intensity was higher In patients •tovated fraction of BL» alao In paHerU over 60 yr* of eg*, and that a durable CR can b*
receiving G-CSF (95% vs 85%) but the difference was not statistically achieved In th**t tubject*. d**pt* th* advanced stage 60 years with a mean age of xx years.There
1986) and 16 with Magrath protocol ( Magrath IT Uppicot 1988) after this time . Median were 289 men and 248 women.
age was 40 y n (IJ-69),19 were mates and 12 females; according to Ann Arbor criteria 7
According to the Arm Arbor staging system 103 patients
pts had in localized stage, 24 advanced stage m or IV; 11 bone marrow involvement and 4
were In stage I, 86 In stage II, 48 In stage III and 300 In
CNS localization. LDH level was above normal value in 17 pts. The clinical characteristics
stage IV. I89 pts. had B symptoms. Extranodal disease was
were similar in the two groups except for stage that is more advanced in p u treated with
Magrath protocol (p<0.01). ATI p u with limited stage received radiotherapy « found In 257 cases. The moat common htstopathotogteal
consolidation after induction chemotherapy. types were centroblastlc and Immunoblastlc h/mphomas.
Results, i ) Stanford mdtnen: all p u with localized stage achieved CR and only one During first line treatment 491 pts. redeved combination
relapsed. OS was 86% with a median FU of 70 months. Only one pt received BMT. Of the chemotherapy ( CHOP/CHOPIDce 377 cases, COP 86, other
8 p u in advanced stage, only one achieved CR and subsequently relapsed. All pu died 28) and 248 pts. had Involved field radiation. Complete
within two years, b) Mapath regimen: only one pu with localized stage was treated and remission was obtained In 292 (56%) of the cases. At 5
achieved a CR. Fifteen p u in advanced stage were treated and CR was achieved in 12 years 158 (29%) pts. are afive without disease, 32 (6%) pts.
(80%), 3 p u did not respond and died within i months. Nine CR's were given BMT (8 are with lymphoma. The survival of pts. with stage I and I I
Downloaded from http://annonc.oxfordjournals.org/ by guest on January 2, 2012
autologous and 1 allogenic) as consolidation treatment. Six are in cominous CR, one died was statistically significant better than pts. with stage III and
of transplantation toxicity and two relapsed. Three CR's did not receive any consolidation IV disease. The causes of death could not be established in
therapy and are still in CR. With a median FU of 18 months OS for p u with advanced all of the cases; 224 (42%) pts. died from rymphoma, 27
stage was 4 3 % (5%) pts. died from other diseases/ other cancers, 7 (1%)
Conclusion. For localized disease the results of two scheme are similar. For advanced stage pts. died from complications and 23 (4%) pts. from
the Magrath protocol obtained better results. The original Magrath protocol was proposed unknown causes.
without any consolidation. Our experience with Stanford schedule suggested us to use BMT
as consolidation b m t t e r o k of BMT Ucomroversial. Randomized protocol are warranted
to clarified this question.
SECOND LINE CHEMOTHERAPY IN HIV-RELATED NON-HODGKIN'S EPIRUBICIN, BLEOMYCrN, VINBLASTINE AND P R E D N I S O N E (EBVP)
LYMPHOMA: EVIDENCE OF ACTIVITY OF A COMBINATION OF VP16, CHEMOTHERAPY (CT) IN COMBINATION WITH ANTIRETROVIRAL THERAPY
AND PRIMARY USE OF G-CSF FOR PATIENTS (PTS) WITH HODGKIN'S DISEASE
MITOXANTRONE AND PREDNIMUSTINE IN RELAPSED PATIENTS
AND HIV INFECTION (HD-HIV).
D. Emmie*.M.Spin**,S. Sandri*.R.Gastaldi0, E. Nigraj,AM. Nosarr\G. Magnani#,
U.TtonkD.Errarae,CGisseIbrechUP.MaroUcttu, YKemcis,A. Ridolfo.M.Mazzetli, A. Lcvis,
E Vaccher* and U. Tirelli*. D. Venai, G. Rossi, M. Span, E. Vaccher for the European Imergroup Study HD-HIV; Aviano
• Aviano Cancer Center, Italy. * University "La Sapienza", Rome - Italy. 5 Hospital Cancer Center-Italy.
"Amedeo di Savoia", Turin - Italy.A Hospital "Niguarda Ca Granda", Milan - Italy. #
Objective: The optimal therapeutic approach lor pts with HD-HIV is unknown. In an attempt lo
University of Parma - Italy.
improve the results that we obtained in a previous prospective study with EBV without G-CSF
Purpose: To evaluate the feasibility and tcti vilyof a second line chemotherapy regimen (Cancer, 73:437-44,1994), mJmuary 1993 we sanedasecond trial consisting of CT.concomitani
consisting of VP16, mitoxanlrone and prednimusine (VMP) in patients with relapsed amiretroviral therapy (AZT or DDI), and G-CSF.
or resistant HIV related non-Hodgkin's lymphoma (HIV-NHL). Methods: Up lo October 1995,27(23 M / 4 F ) consecutive previously untreated pu (median age
Patients and methods: Twenty-one patients were consecutively treated. Thirteen 33,range2M9 years) with HD-HIV were enrolled. Median performance status was 1 (range 1-3).
At diagnosis of HD, 7 (26%) of pts had AIDS, 3 (11 %) ARC, and 17 (63%) were asymptomatic.
patients were resistant to primary chemotherapy and eight patients had relapsed after Eigroy-Tivepcrcemc/puhadBsyraptcnsaiHDrjre9eniaiion.PunsxrWdE70rng/rn2Lv. on day
first complete remission (CR). VP16 and prednimustinc were both given orally at dote* l,B10mgAn2Lv.ondayl,V6mgfatf Lv.ondaylarKlP40mgAn2p.afrornday ltodayS.Counci
of 80 mg/m 2 daily for 5 days, and mitoxantrone was given i.v. at a dose of 10 mgAn2 were repealed every 21 days for six cycles. ACT (250 mg x 2/day) or DDI (200 or 300 m j x 2/day),
on day 1; cycles were repeated every three weeks. when AZT was previously used, were given orally from the heginning of CT. G-CSF was given m
the dose of 5 mcg/xgMay i c from day 6 to day 20 in all cycle*.
Results: Nineteen out of 21 patients are evaluate forresponse.The median number of
Remits: ClinJco-pmhologJc characteristics of pu and response to thenpy are shown in the labtc
cycles actually administered was 2 (range 1-5). A CR occurred in 5 out of 19 patients
(26*; exact 95% confidence interval: 9% to 51%). Four of these CRs were observed • pu CD4+ at diagnosis Subtype Stage Response DFS
in the 7 evaluaWe relapsed patients. Out of 45 cycles evaluaWe for toxicity, severe cmercdVfevoluablc median I (range) MC&LD III & IV Oft CR ot2vn
ncutropenia (<500Anl) occurred in 19 (42%) cycles and severe Ihrombocytopcnia 27/21* 187(6*12) 18(66*) 22(82%) 90% 71% 4 3 %
(<25.000Anl) In 6 (13%) cycles. One toxic death occurred due to a sepsis during • 6 pts are still on treatment.
neutropenia. The overall median survival was 2 months (range, <1-13); the median Toxicity was moderate with grade 3-4 leukopenia and thrombocytopenia in 7 (33%) and in 2 (10%)
survival time for the 5 patients with CR (13 months, range 6-13) was statistically pu respectively. Fifteen out of 21 pts received AZT and 2 pu received DDL Only 6 (28%) pu had
signi fleam longer (pMtSXH) than that observed in patients without CR (2 months, range oppenuniaic infection* (01). duringor after CT (median follow-up, 14 months). No change of
therapy. Six out of 15 (40%) pu who achieved a CR relapsed. Overall, HD progression alone and
Conclusion: Although the overall prognosis of patients with resistant and relapsed in association with 01 was the cause of death in 46% andfa15% of pu respectively. The median
HI V-NHL is very poor, palliative therapy with VMPcan be effective and relatively safe. survival was 14 months with an actuarial survival me of 33% at 24 months.
Prolonged survivals have been observed in some patients who had relapsed after initial i-nmhinM mftrryo wm frftiht* Hnwrvrr, ^llh^igh \hr fT» M f rinujnrri mm
chemotherapy. rm
satisfactory, the number of rebmjed pts was Wjh and overall median survival was not different C a
our previous experience or from literature. Taking in constdemion the moderate toxicity, we are
Supported by AIRC *95 grants. cunentlyaiaskien^higherdcaesc/CTatsrjorteriniervabwuhthesupponofG-CSF. Supported
by AIRC "95 and ISS "95.
9. Aggressive lymphoma 165
ASSOCIATION O F ZIDOVUDINE (AZT) AND METHOTREXATE (MTX) EVALUATION O F RECOMBTNANT GRANULOCYTE COLONY-STIMULATING
FOR TREATMENT OF HIV-RELATED NON-HODGKIN'S LYMPHOMAS FACTOR (G-CSF) AS PRIMARY PROPHYLAXIS IN HIV-RELATED NON-
HODGKIN'S LYMPHOMA (NHL) TREATED WITH PROMACE-CYTABOM (PR-CY)
(NHL).
F Ghcrlinzcni, P Tori, P Mazza*, 0 Corooado", P Cos»iglioU°, MC Miggiano, PL G. Rossi, A Ro, A. Donisl, S. Casari, R. Stellini, G.P. Cadeo , G.P. Carosi. Sezione
Zinzani, M Magagnoli, F Chiodo", S Tura. Ematologia, Clinics Malattte Infettiva, I Divisions Malame Irrfetttve, Spedali Crvili,
Inst Hematology "Seragnoli", University of Bologna; •Dept. Hematology SS. UnJversita degli Studi, 25100 Brescia .Italy.
Annunziata Hospital, Taranto; "Inst. Infectious Disease, Univeoity of Bologna, Italy.
Growth factor support in HIV-related NHL is generally recommended, but its cost-
effecUveness has not been clearly established. W e compared the effects of G-CSF
Zidovudinc (AZT) can possess a significant anliprolifcrative activity when support In two consecutive groups of patients (pts) with HIV-related NHL treated at a
combined with drags that disrupt "de novo" thymidylate synthesis, such as 5- sixjto institution with the same chemotherapy (CT) program PR-CY, +/- G-CSF.
fluorouracil or MTX. HIV-related NHL are constantly associated with a very poor PR-CY was given to 33 HIV+ pts with aggressive N H L The 21 ptt diagnosed after
prognosis irrespectively of the regimen of conventional chemotherapy. 01/01/92 also received G-CSF at the fixed dose of 300ug/sc daily from day 9 to day
In January 1993 we started a clinical trial with the objective to evaluate both 20 of each cycle. The 12 earlier pts never received G-CSF and acted as controls. At
NHL (flagnosls, G-CSF treated pts had significantly more advanced HIV disease
efficacy and tolerance of the combination AZT + MTX m HIV-relatcd NHL. 29
compared to controls ( CD4+ oount <0.100/ml in 7 1 % vs 17%; P O . 0 0 3 ) and lower
patients (pti) (22 males, 7 females) have so far been enrolled in the trial, mean age is WBC counts (3.84 vs 6.66/ml; P<0.03).CIWcopathotoglcal features of NHL were
34.5 years (range 23-49); 13 (32%) are drug abusers, 19 (65%) had less than 100 comparable. A total of 137 cycles were evaluaWe, 85 with and 52 without G-CSF G-
CD4/mmc. The most represented hiitoJogic subtypes are: diffuse large cell lymphoma CSF support significantly decreased the frequency of day-1 drug dose reductions
(14 pts), Burkitt (7 pti); stage IV was present in 21 pU (72%). 13 pu (45%) had from 3 7 % In controls to 8% in treated pts (P
bulky disease. Treatment plan includes three consecutive courses of MTX, 1 g/m 3 from 56% of cycles in controls to 9% in treated p u ( P O . 0 0 1 ) ; it improved the actually
delivered total doses of adrtamydn, cydophosphamide and etoposide (P<0.02), but
(days 1, 8 and 15) + oral AZT 2 g/m 3 (days 1. 2 and 3), 4 g/m3 (days 8, 9 and 10)
did not affect the frequency and duration of fever and of hospttalizatton. CR rate and
and 6 g/m 1 (days 15, 16 and 17). Folinic acid is administered 12 hours after each survival were worse among G-CSF treated pts. However, this result was related to
dose of MTX. From the 11th patient on, the treatment was continued with three more their more advanced HIV disease and differences were not significant when pts were
courses in case of complete or partial response. Out of 25 evaluable pu, 11 (44%) stratified according to their CD4+ count Among pts with a CD4+ count O.IOXVml,
achieved a complete remission (CR) and 9 (36%) a partial response (PR) (overall day-1 drug dose reductions and CT delay occurred in 10% of cycles with G-CSF
response rate •» 80%). In 3 pts CR duration is lasting more than 24 months. Median compared to 8 0 % without G-CSF (P<.001).
follow-up of the responden is 12 months. Grade I [1-1V neutropenia was observed in In conclusion, G-CSF support significantly improved dose-intensity In patients
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23/112 courses (21%). G-CSF was administered in 65 courses (58%). No patient treated with aggressive CT for HIV-related NHL, particularly in those with a CD4+
showed grade III-1V extrahematological toxiaty; only 1 patient developed an count O.100/ml, a subset which can hardly tolerate full-dose CT. However the
opportunistic infection. increased dose intensity achieved with G-CSF did not result in a better clinical
outcome and the major determinant of prognosis remained the stage of the
In conclusion, these data show that AZT + MTX combination is effective and underlying HIV disease.
safe in HIV-related NHL.
CUNICO-PATHOLOGIC CORRELATIONS IN 120 PATIENTS (PTS) WITH I11V- VlTAMlN-D-MEDtATED HYPERCALCEMIA A3 THE PRESENTING SYMPTOM OF
RELATED-SYSTEMIC-NON-HODGKIN'S LYMPHOMA (HIV-NHL): A T-CELL IMMUNOBLASTK LYMPHOMA.
MONOINSTrrUTIONAL STUDY.
G. Nasti*, E. Vaccber*. D. Emmte •, M. Spina', M. Tavio*. C. Snoonelli •, S. Saniarossa*. G. J.F. Seymour and D. Manor, Department of Clinical Haematology and Medical
Di Gennaro*. A. Carbone ° and U. TireUi*. • Division of Medical Oncology and AIDS; • Oncology, The Royal Mefooume Hospttal, Parkvflle 3050, Australia.
Division of Pathology - Avlano Cancer Center - (PN) - Italy.
HypercaJcemla Is an uncommon complication of non-Hodfjkin's tymphomas
HTV-NHLicpmtiuan betei uyo icons group of diseases, characterised by the presence of distinct (NHL), occurring in up to 15% of patients with Intermediate- or high-grade
molecular-paihological entities, but overall considered associated with a poor outcome. Few dteease. However, In patients with HTLV-1-related adult T-cell leukemia /
extensive studies on clinico-paihological correlations have been conducted. In this suidy we
lymphoma (ATLL) hypercafcemla ts present in more than 80% of cases and is
ouun ined the relationship between pathological and cli nical data obtained from aroonoisilutional
series of 120 pu with HI V-NHL, diagnosed and treated with chemotherapy from September 1987 known to be mediated through the systemic actions of parathyroid hormone-
toJuly 1995. AD cases were intermediate-high grade NHL according u the WP. and the updated related protein (PTHrP) which also mediates the humoral hypercalcemla of
Kiel classification. The main clinico-paihological correlations are reported in uble. most soBd tumours. In contrast, recent studies suggest that ectoptc production
Histo Ionic OTHIW of activated vltamln-0 (calcltrlol) by non-maBgnant macrophages within
G H J KiALC* Miscell P rymphomatous Ussue Isresponsttrfefor the hypercalcemla compficating B-cen
(n»18) (n*23) (n*39) (n'14) (n°27) value NHL Few patients wtth HTLV-1 negative T-cell NHL and hypercafcemia have
(*) (*) (*) (*) (*) been evaluated, and the mechanism of the hypercalcemla In these cases Is
unknown. A 71 y.o. woman presented with symptomatic hypercatcemla and
AGE yrs (mean, ± SD) 36113 38±8 34±g 38±12 37±11 NS
PRIOR AIDS 17 35 26 39 30 NS diffuse bone pain; serum C a ~ 3.1 mmol/l [normal: 2.1 - 2.6]. Nuclear bone
CD4 COUNT <100/mm3 69 0.009 scan had multiple areas of abnormal uptake suggestive of "metastases". She
33+ 59 rt* 63*
had no adenopathy or organ enlargement cfinicaOy or wtth Imaging, and no
STAGE m-IV 67 48 82 69 63 0.08
CR~RATE 56 24 41 25 16 NS evidence of a primary tumour sKe. Bone marrow biopsy was normal. Serum
SURVIVAL mo (median) 16.4* 6\6 8 9.8 6.7" 0.08 PTH was suppressed and PTHrP was undetectable. Serum caJcttrtol was
A
markedly elevated: 150 pmoM [expected: < 75). HfV and HTLV-1 serology were
KiALC » Ki 1 - anaplastic large celt + G vs ALC p • 0.05; * G vs Mis p - 0,05; • J vs H p « 0.02; negative. A biopsy of a rib lesion revealed T-ceD immurtoblastic NHL, stage
** Complete remission; • GviH p • 0.01 ;**Gvs Mis. p - 0.01.
tVA, International Index score « 3. The hypercalcemla promptly normalised
Our preliminary results show: 1) a relationship between histologic subtypes of NHL and degree following CHOP therapy and CR was attained after 7 cycles. Cafcftrlol levels
of immunodeficiency, with Burtdtfl and G (centroblastic) NHL »««nrijii-H wiili a significantly returned to normal. The patient remains In ongoing CR 12 months after
higher CD4 level; 2) a significant better outcome for NHL of the G subgroup than H subgroup. presentation. This case iustrates that the hypercateemia of T-cell NHL may be
This finding sujgestthat G NHL should not be included with H (immunobUstic) in the same vtamkvO-medSateu, as in B-NHL, rather than PTHrP-mediated as In HTLV-1+
category of diffuse large cell NHL, (Harris eta], 1994), since H NHL is attoriited with poor ATLL. Further, rymphoma should be considered as a cause In patients
outcome. presenting wtth hypercafceirda and muSiple bone "metastases".
Supported by ISS and ADtC grams.
166 9. Aggressive lymphoma
621
GLOMERULONEPHRITIS IN NON-HODGKIN-LYMPHOMA
REPORT OF 3 CASES AND LITERARY REVIEW
J. Zahner, D. Bach, B. Grabensee, W. Schneider. Medizinische
Klinik, Heinrich-Heine-Universitat, D - 40225 Dusseldorf
The association of Non-Hodgkin-Lymphoma (NHL) and glome-
rulonephritis (GN) is well-known for many years. Whereas in
Hodgkin's disease, minimal change GN is mainly observed, in
NHL various forms of GN are found.
We describe 3 cases of NHL-associated GN: 2 patients, one with
chronic lymphatic leukemia (CLL) and one with cutaneous T-cell
lymphoma, developed IgA nephritis, in a third patient with CLL
membranous GN was observed. 2 cases showed impaired renal
function and 2 had nephrotic syndromes, which improved after
treatment. In 2 cases GN and NHL developed simultaneously, in a
third lymphoma was followed by GN after 3 years.
Although the pathogenetic relationship between NHL and GN is
not fully understood, an immunological link has been postulated.
The high number of cases reported in the literature suggest inter-
dependence. Including our 3 patients we found 71 cases of NHL-
associated GN in the literature. NHL-associated GN is observed
more often in men than in women and more frequently in low-
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grade NHL - especially in CLL - than in high-grade NHL.
Compared to GN in M. Hodgkin, NHL-associated GN shows
higher rates of impaired renal function and nephrotic syndrome.
The majority of NHL do not show any predisposition to a special
type of GN, only in cutaneous lymphoma IgA nephropathy
predominates. Apart from simultaneous manifestation, sometimes
GN precedes NHL or develops after the onset of NHL.
9. Aggressive lymphoma 167