Single agent laromustine (VNP40101M), a novel alkylating agent, has significant
activity in older patients with previously untreated poor-risk acute myeloid leukemia.
1
Gary J. Schiller, 2Susan M. O'Brien, 3Arnaud Pigneux, 4Daniel J DeAngelo, 5Norbert
Vey, 6Jonathan Kell, 7Scott Solomon, 8Robert K. Stuart, 9Verena Karsten, 9Ann L. Cahill,
10
Maher X. Albitar, 11Francis J. Giles
1
David Geffen School of Medicine at UCLA, Los Angeles, CA; 2The University of Texas
M.D. Anderson Cancer Center, Houston, TX; 3Hopital Haut Leveque, Bordeaux,
France; 4Dana-Farber Cancer Institute, Boston, MA; 5Institut Paoli-Calmettes,
Marseille, France; 6University Hospital of Wales, Cardiff, UK; 7Northside Hospital, BMT
Group, Atlanta, GA; 8MUSC Hollings Cancer Center, Charleston, SC; 9Vion
Pharmaceuticals, Inc., New Haven, CT; 10Quest Diagnostics Nichols Institute, San
Juan Capistrano, CA; 11 CTRC at The University of Texas Health Science Center, San
Antonio, TX
This study received research support from Vion Pharmaceuticals, Inc, New Haven, CT
Address reprint requests to Francis J. Giles, MD, CTRC at The UT Health Science
Center, 7979 Wurzbach Road, Mail code 8026, Urschel Tower, Suite 600, San Antonio,
TX 78229 Phone: 210 450 3838. Fax 210 450 9823 Email: [email protected]
Running head: Laromustine in elderly with previously-untreated poor-risk AML
Presented in part at ASCO Annual Meeting 2008 – May 20 2008: Abs 7026
1
Abstract
Purpose: An international phase II study of laromustine (VNP40101M), a
sulfonylhydrazine alkylating agent, was conducted in patients ≥60 years with previously
untreated poor-risk acute myeloid leukemia (AML).
Patients and Methods: Laromustine 600 mg/m2 was administered as a single 60minute intravenous infusion. Patients were ≥ 70 years or ≥ 60 years with at least one
additional risk factor – unfavorable AML karyotype, ECOG Performance Score (PS) of
2, and/or cardiac, pulmonary or hepatic comorbidities.
Results: Eighty-five patients (median age 72 years (60 to 87)) were treated. Poor-risk
features included: Age ≥ 70, 78%; adverse karyotype, 47%; PS 2, 41%; pulmonary
disease 77%; cardiac disease 73%; hepatic disease 3%. 96% of patients had ≥ 2 risk
factors, 39% ≥ 4. The overall response rate (ORR) was 32%: 20 patients (23%)
achieving complete response (CR), 7 (8%) CR with incomplete platelet recovery. ORR
was 20% in patients with adverse cytogenetics; 32% in those ≥70 years; 32% in those
with PS of 2; 32% and 34%, in patients with baseline pulmonary or cardiac dysfunction
respectively, and 27% in 33 patients with ≥4 risk factors. Twelve (14%) patients died
within 30 days of receiving laromustine therapy. Median overall survival was 3.2
months, with a 1-year survival of 21%; the median duration of survival for those who
achieved CR/CRp was 12.4 months, with a 1-year survival of 52%.
Conclusion: Laromustine has significant single-agent activity in elderly patients with
poor-risk AML. Adverse events are predominantly myelosuppressive and/or respiratory.
Response rates are consistent across a spectrum of poor-risk features.
2
Introduction
Elderly patients with AML have a very poor prognosis, attributable to having both more
resistant disease and relatively poor tolerance of cytotoxic agents.1In contrast to
younger patients, treatment for elderly patients with AML has not improved over recent
decades.1-3 The majority of older patients with AML are not offered current standard
induction regimens and survival for those who are treated is very poor.4-6 Laromustine
({VNP40101M; Cloretazine, OnriginTM}, Vion Pharmaceuticals Inc, New Haven, CT) is a
1,2-bis(sulfonyl)hydrazine with broad spectrum antitumor activity in preclinical models.720
Laromustine is initially activated to yield 90CE [1,2-bis(methylsulfonyl)-1-(2-
chloroethyl)hydrazine] and methylisocyanate. 90CE rapidly produces an alkylating,
chloroethylating species, similar to the species generated by BCNU
[carmustine]).11,20BCNU and laromustine produce different decomposition products as
laromustine does not yield hydroxyethylating, vinylating, or aminoethylating species.
The chlorethylating species responsible for laromustine's alkylation is relatively specific
to the O6 position of guanine, while BCNU, unlike laromustine, also alkylates the N7
position of guanine as is more typical of most alkylating agents.11,21 Laromustine yields
over twice the molar yield of DNA cross-links than the nitrosoureas. Drugs that cause
primarily N7 alkylations exhibit one thirtieth of the anticancer activity and the same
mutagenic potential as their counterparts that form both N7 alkylations and crosslinks.14,18 Laromustine does not generate hydroxyethyl alkylations of the O6 position of
guanine – these lesions are considered to be carcinogenic but therapeutically
unimportant.14,20 Laromustine also inhibits the nucleotidyl-transferase activity of purified
3
human DNA polymerase beta (Pol beta), a principal enzyme of DNA base excision
repair (BER).22 Alkylated DNA is often repaired via BER in vivo. Inhibition of the
polymerase activity of Pol beta may account for some of the synergism between
laromustine's two reactive subspecies in cytotoxicity assays. Laromustine has
significant activity against hematologic malignancy–derived cell lines, including those
resistant to other alkylating agents, and has significant activity in animal leukemia
models.12,23-25
Myelosuppression is dose-limiting in patients with solid tumors receiving laromustine
with minimal attendant significant nonhematologic toxicity.26,27 In a phase I study of
laromustine in patients with refractory leukemia, mild reversible infusion-related
toxicities were the most frequent adverse events, occurring in 24 patients (63%) on the
first course.28 Dose escalation was terminated at 708 mg/m2 because of prolonged
myelosuppression; 600 mg/m2 was the recommended phase II study dose, with no
significant extramedullary toxicity at this dose level. The combination of laromustine
and cytarabine was also studied in patients with refractory leukemia.29 Complete
responses (CRs) were seen at laromustine dose levels 400 mg/m2 in 10 (27%) of 37
patients. Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen
with 500 and 600 mg/m2 of laromustine combined with a 4-day 1.5 gm/m2/d continuousinfusion cytarabine schedule, but not with the equivalent 3-day schedule.
A phase II study was conducted in patients with previously untreated non-favorable
karyotype AML/high-risk MDS 60 years of age at the time of therapy.30 One hundred
and thirty one patients, median age 72 years, received laromustine as a single 600
4
mg/m2 intravenous infusion. Performance status was 2 in 34 (26%) of patients. Overall
response rate was 31% with 31 patients (24%) achieving CR, 9 (7%) CR with
incomplete platelet recovery (CRp). Response rates in 54 de novo AML patients was
44%, 37% in 68 patients with intermediate-risk and 26% in 54 patients with
unfavorable-risk cytogenetics. An international Phase II study of laromustine was
performed in older patients with AML and prospectively defined additional poor-risk
factors.
5
Patients and methods
The study was reviewed and approved by institutional review boards at all participating
institutions. All patients provided signed informed consent indicating that they were
aware of the investigational nature of this study.
Patient Eligibility
Patients with previously untreated non–acute promyelocytic leukemia (APL) AML, age
60 years, were eligible. Patients were allowed to have active controlled infection
including chronic hepatitis and/or known CNS leukemia. Eligible patients had at least
one additional risk factor – unfavorable AML karyotype (Table 1), ECOG Performance
Score (PS) of 2, age ≥ 70 years, and/or cardiac, pulmonary or hepatic comorbidities
which were defined as per the Hematopoietic Cell Transplantation Comorbidity Index
(HCT-CI).31 Cardiac dysfunction was defined as ejection fraction≤ 50%, history of
significant coronary artery disease (one or more vessel stenosis requiring medical
treatment, stent placement or surgical bypass graft), history of CHF or MI, significant
arrhythmia including atrial fibrillation or flutter, sick sinus syndrome, or ventricular
arrhythmia, and/or valvular heart disease (excluding mitral valve prolapse). Pulmonary
dysfunction was defined as DLCO and/or FEV1 < 80% and/or dyspnea on slight activity
or at rest or requiring oxygen. Hepatic dysfunction was defined as chronic hepatitis
and/or liver cirrhosis. As the formulation of laromustine contains 30% ethanol,
concurrent treatment with disulfiram was not allowed.
Treatment and Study Design
Patients received laromustine 600 mg/m2 on day 1 administered by intravenous
6
infusion using a polyethylene-lined administration set in a peripheral or central vein.
Patients were pretreated with antihistamines and antiemetics to prevent transient
infusion-related reactions. Patients were eligible to receive a second cycle of
laromustine induction therapy if they achieved less than CR but some marrow
improvement after the first cycle. For patients in CR after a first/second induction cycle,
or PR after a second, at least one consolidation cycle of continuous infusion cytarabine
at a dose of 400 mg/m2/day for 5 days was to be administered. Toxicity was graded
using the National Cancer Institute Common Toxicity Criteria (version 3.0). All patients
who received any therapy on study were considered assessable for toxicity and
response.
Response and Prognostic Criteria
CR was defined as normalization of the blood and bone marrow with 5% blasts, a
granulocyte count 1 x 109/L, and a platelet count 100 x 109/L. CRp was as per CR,
but with platelet counts remaining <100 x 109/L, and independence of platelet
transfusions was defined as the ability to maintain a platelet count of 20 x 109/L.
Marrow slides used for diagnosis and response evaluation were reviewed by an
independent pathologist at a central laboratory.
Statistical Analysis
A two-stage optimal minimax design was used.32 If ≤21 of 77 patients achieved CR, the
hypothesis that the ORR is ≥35% was to be rejected. Survival was measured from the
day of laromustine treatment to death as a result of any cause. Distributions of overall
survival were estimated by the method of Kaplan and Meier. Quantitative factors were
7
treated as continuous variables in regression analyses, but grouped when necessary
for descriptive tables and figures.
Results
Patient Characteristics
Eighty-five eligible patients were enrolled onto the study between May 2006 and
December 2007. Sixty-two (73%) patients were classified as AML not otherwise
classified. Twenty (24%) patients had a diagnosis of AML with multilineage–dysplasia
without antecedent MDS based on morphologic findings. Two patients had evidence of
prior MDS/MPD and one patient had acute biphenotypic leukemia. Forty (47%) patients
had an unfavorable AML karyotype. Patient baseline characteristics are summarized in
Table 2. Fifty patients (59%) were male. The median patient age was 72 years (range,
60 to 87 years), sixty-six (78%) patients were older than 70 years; performance status
was 2 in 35 patients (41%). Sixty-five patients (76%) had pulmonary dysfunction, 62
(73%) cardiac dysfunction, and 3 (4%) had hepatic dysfunction at study entry (Table 3).
Among patients with cardiac disease, 30 (48%) had one cardiac risk factor, and 32
(52%) had multiple cardiac risk factors. Regardless of the number of cardiac risk
factors present, a score of one was assigned to each patient with cardiac disease.
Among patients with pulmonary dysfunction, 22 (34%) had moderate disease, with
DLCO/FEV1 >65 and <80%, whereas 43 (66%) had severe disease with FEV1 ≤65%
and/or dyspnea at rest and/or requiring oxygen. Three (4%) patients had a single poor-
8
risk factor (2 with age ≥ 70 year, 1 with pulmonary dysfunction). The majority of
patients (96%) had 2 or more risk factors.
Toxicity
Infusion Reaction
Ninety-nine cycles of laromustine therapy were administered. Infusion reactions were
reported as adverse events in 21 (25%) patients during treatment with laromustine
induction cycle 1 or cycle 2. Hypotension was the most frequently reported event in 7
patients, followed by headache reported in 5 patients, nausea and vomiting in
3 patients each, and flushing, malaise and rash in 2 patients each. All of the events
were mild or moderate in intensity and resolved within 24 hours (most within a few
hours). In 3 patients interruption of laromustine infusion was required due to events of
headache, lethargy or pruritus. The events resolved and the infusions were completed
in all cases.
Myelosuppression
Grade 3/4 myelosuppression after first induction with laromustine occurred in almost all
patients with 82% and 75% of patients exhibiting Grade 4 neutropenia or
thrombocytopenia respectively. Eighteen of 27 patients who had baseline neutropenia
of grade 0 to 3 experienced grade 4 neutropenia after treatment. Forty-three of 63
patients who had baseline grade 0 to 3 thrombocytopenia experienced grade 4
thrombocytopenia after treatment. For patients who achieved CR/CRp, the median
9
time to granulocyte counts ≥0.5 x 109/L was 35 days (range 3-70) and to platelet count
≥50 x 109/L was 35 days (range 15-79). The median time to granulocyte recovery of
≥1.0 x 109/L was 38 days (range 8-79) and median time to platelet recovery ≥100 x
109/L was 35 days (range 28-70).
Adverse Events
Grade 3/4 non-hematologic adverse events that occurred within 42 days after induction
cycles 1 or 2 with laromustine and were considered potentially related to laromustine
are summarized in Table 4. Grade 3/4 febrile neutropenia occurred in 15 patients.
Gastrointestinal events such as nausea and vomiting or diarrhea were frequent but
generally mild or moderate in intensity. Only one grade 3 event of intermittent diarrhea
occurred 19 days following induction cycle 1 with laromustine. Mucositis was infrequent
(9%) and primarily of low grade; one grade 3 event of mucosal inflammation occurred
27 days after laromustine treatment. Grade 3/4 non-infectious respiratory events were
observed in 6 patients of which 3 occurred after 2 induction cycles with laromustine.
The onset of dyspnea or pleural effusions was between day 23 and 117 from the first
treatment with laromustine. The radiologic findings in 2 cases were described as
ground-glass opacities. In 2 patients the pulmonary events resolved after corticosteroid
administration. Infectious events considered possibly related to laromustine occurred in
22% of patients.
Twelve (14%) patients died within 30 days of receiving first induction with laromustine,
all deaths occurred while patients were pancytopenic. AML progression with or without
10
infection was the primary cause of death in 6 patients. Two patients died with severe
pneumonia and one patient with severe neutropenic sepsis. Two patients had Grade
3/4 renal dysfunction, one died on study day 4 with tumor lysis syndrome and one, who
also had pneumonia, died on study day 29. One patient died from acute respiratory
distress syndrome on study day 17. Five responding patients died within 30 days of
receiving cytarabine for consolidation treatment, two events occurred following a
second consolidation cycle of cytarabine. These deaths also occurred in patients with
pancytopenia and were reported to be due to infection (n=2), ventricular fibrillation
(n=1), cardiac arrhythmia (n=1) and cerebral hemorrhage (n=1).
Response
Twenty-seven patients (32%) achieved CR (20, 24%) or CRp (7, 8%). The majority of
remissions were achieved after a single induction treatment with laromustine. Of 14
patients who received a second cycle of laromustine therapy, 1 achieved CR. Eighteen
and four patients received a first and second consolidation cycle with cytarabine for 5
days, respectively. Two patients received non-protocol specified consolidation therapy
– one a course of tipifarnib and a second a course of idarubicin and cytarabine. The
CR rates by individual risk group are summarized in Table 5. The ORR was 20% in
patients with adverse cytogenetics; 32% in those ≥70 years; 31% in those with PS of 2;
32% and 34% in those with pulmonary or cardiac dysfunction respectively at study
entry. The ORR was 27% in 33 patients (39%) with ≥4 risk factors.
11
Treatment outcome by number of risk factors is presented in Table 5. The response
rate remained consistent as risk increased within the study population. Overall survival,
which was comparably prolonged in CR and CRp, is summarized graphically in Figure
1. The median overall survival was 3.2 months in all patients (2.1 months in nonresponders and 12.4 months in responders). The percentage of patients that were alive
12 months after receiving therapy was 21% for all patients (9% in non-responding
patients and 52% in responding patients). Among patients who did not achieve a CR
with laromustine therapy, fifteen (26%) received subsequent re-induction therapy,
which resulted in remission in 3 patients.
Discussion
The results of the current study confirms and extends the observation made in a prior
study, with broader patient eligibility criteria, that single agent laromustine has
significant activity in older patients with poor prognosis previously untreated AML.30
The treatment of elderly patients with AML remains a very significant challenge.1-6 A
combination of inherently biologically more resistant disease, including P-glycoprotein
overexpression and increased frequency of both adverse cytogenetic and molecular
makers, as well as an increased incidence of patient baseline comorbidities, are
associated with very poor results following current standard AML induction regimens.3,6
There are inherent difficulties in the assessment of a novel approach in a cancer
population for which no standard therapy exists and/or in which available therapies are
ineffective and/or very poorly tolerated. As a prior international Phase II study had
identified a consistent CR rate associated with single agent laromustine therapy in
12
elderly patients with AML30, the current study focused on patients with disease and/or
clinical features known to be associated with a particularly poor prognosis. The study
population thus contained a large percentage of patients whose baseline cardiac,
pulmonary, and/or hepatic comorbidities rendered them unlikely to receive
anthracyclines and/or cytarabine – the common standard cytotoxic agents included in
AML induction regimens. A low dose cytarabine (LDAC) regimen was recently
randomized versus hydroxyurea in older patients with AML considered unfit for
standard induction therapy.6 LDAC, while demonstrating superior response rates and
overall survival to hydroxyurea, was not associated with achievement of CR in patients
with adverse cytogenetics and/or poor performance status. In contrast, laromustine
therapy results in CR and prolonged survival in patients prospectively selected for poor
prognosis AML. A direct comparison between LDAC and laromustine would require a
randomized study which would need to be performed in only better prognosis patients
– the issue there would be whether LDAC can be considered a reasonable regimen to
offer such patients in view of its low ability to achieve CR.
In AML, older age, adverse AML karyotype, and poor performance status are poor-risk
features.3,5,33,34 While comorbidity is acknowledged to be both an independent adverse
prognostic factor in elderly patients with AML, and to be not fully accounted for in
performance score analysis35, it is a challenge to define prospectively. The HCT-CI has
been shown to be predictive of both early mortality and overall survival in elderly
patients receiving myelosuppressive AML induction therapy.36 The HCT-CI has also
been validated in patients with myelodysplastic syndromes (MDS).37 In the currently
reported study definitions for pulmonary, cardiac and hepatic dysfunction from the
13
HCT-CI were prospectively used to define patients with baseline organ dysfunction.
Laromustine retained activity despite the presence of multiple comorbidities even when
these were present in organ systems (cardiac, pulmonary), as conditions mitigating
against the use of anthracycline/cytarabine induction regimens. The incorporation of
formal comorbidity scales in therapeutic studies in elderly AML facilitates comparisons
between approaches. While the HCT-CI has been shown to be reproducible as a
prognostic determinant in patients with hematological malignancies treated at different
institutions,38 other recently reported prognostic scales for older patients with AML also
merit further study.33,39 This study data also confirm the pattern of extramedullary
toxicity of laromustine at doses that are both myelosuppressive26,27 and capable of
significant leukemia tumor burden reduction.29,30,40,41 As anticipated with an alkylating
agent, myelosuppression and it’s consequences comprise the major toxicity of
laromustine. Medically important respiratory events marked by dyspnea that can
develop weeks to months following therapy have been observed in a few patients and
can resolve with steroid treatment. Events commonly associated with leukemia
induction treatment, such are mucositis, severe gastrointestinal toxicity and alopecia
occurred infrequently and at low grades. Cardiac events were uncommon. The
relatively constant early death rate observed in patients with multiple risk factors
indicates that the presence of these factors should not preclude administration of
laromustine therapy. Some deaths were observed following cytarabine consolidation
associated with myelosuppression suggesting that this consolidation schedule might
not be optimal for some elderly patients with poor-risk features. Optimal consolidation
approaches have not been established in the elderly population with AML due to the
14
paucity of both patients in response and of nontoxic agents with anti-leukemia activity.
Such agents are now in development and approaches that may help to prolong
laromustine-induced CR significantly could include LDAC,6 hypomethylating agents,42
FLT3 inhibitors,43 vascular endothelial growth factor antagonists,44 and/or vaccines.45
The majority of patients with AML over 60 years of age do not receive the standard
AML induction therapies given to younger patients.46,47 Increasing comorbidity is
significantly associated with a reduced chance that a patient will be offered a cytotoxic
AML induction regimen.46,48 The patients treated with laromustine on this study were
chosen for multiple poor prognosis features, including the first prospective use of the
HCT-CI to quantify baseline comorbidity. No data has been published on the use of
standard AML induction regimens in an elderly patient cohort prospectively defined as
in the currently reported laromustine study. Recent randomized studies in potentially
similar populations have involved LDAC, hydroxyurea, or supportive care as control
arm therapies.6,49 Recent in vitro data have shown synergistic activity of laromustine
when combined with standard AML induction agents on the proliferation, viability and
apoptosis of AML cell lines and blast cells from patients.25 Future studies of the
combination of laromustine with standard induction anthracycline/cytarabine regimens
are warranted, as are those investigating whether laromustine can be substituted for
one or more of the agents within these regimens.41
Novel agents being investigated in older patients with AML, including clofarabine,
decitabine, tipifarnib, and CP-4055, warrant investigation in combination regimens with
15
laromustine.42,50-52 Laromustine offers a new therapeutic option for older patients with
poor-risk AML.
16
Table 1. Cytogenetic risk group classification
Risk group
Intermediate
Unfavorable
Karyotype
Normal
+6, -Y, del(12p)
del (5q) / - 5q
-7 /del (7q)
Abnormalities involving (3q),
(9q), (11q), (20q), (21q)
abn (17p)
t (6;9)
t (9;22)
complex (≥3 unrelated
abnormalities)
17
Table 2. Baseline characteristics of patients treated on study
N (%)
ECOG
PS = 2
N (%)
Cardiac
Dysfunction N
(%)
Pulmonary
Dysfunction
N (%)
0
(0%)
2
(67%)
0
(0%)
0
(0%)
1
(33%)
0
(0%)
18
(21%)
7
(39%)
13
(72%)
2
(11%)
8
(44%)
6
(33%)
0
(0%)
≥3
64
(75%)
33
(52%)
51
(80%)
33
(52%)
54
(84%)
58
(91%)
3
(5%)
Total
85
40
(47%)
66
(78%)
35
(41%)
62
(73%)
65
(76%)
3
(5%)
No. Risk
Factors
No.
Patients
Unfavorable
Cytogenetics
N (%)
1
3
(4%)
2
Age
≥ 70
Hepatic Dysfuncti
N (%)
18
Table 3: Baseline HCT-CI comorbidity distribution
Comorbidity
Cardiac
Severe Pulmonary
Infection
Arrhythmia
Psychiatric Disturbance
Diabetes
Moderate Pulmonary
Solid Tumor
Mild Liver
Heart Valve disease
Obesity
Cerebrovascular Disease
Moderate/Severe Liver
Peptic Ulcer
Rheumatologic
N=85
39 (46%)
43 (51%)
31 (36%)
36 (42%)
18 (21%)
21 (25%)
22 (26%)
11 (13%)
14 (16%)
17 (20%)
13 (15%)
2 (2%)
3 (4%)
3 (4%)
2 (2%)
HCT-CI = Hematopoietic cell transplantation-specific comorbidity index
19
Table 4. Potentially Laromustine-related adverse events occurring in > 5% of
patients*
Preferred Term
Grade Grade Grade
1-2
3
4
14
1
Overall
Febrile Neutropenia
12
27 (31.8%)
Nausea
24
Hypotension
13
1
14 (16.5%)
Pyrexia
13
1
14 (16.5%)
Fatigue
12
1
13 (15.3%)
Diarrhea
12
1
13 (15.3%)
Vomiting
9
Mucosal inflammation
7
Headache
8
Pleural Effusion
6
2
Dyspnea or Hypoxia
3
3
Peripheral edema
6
6 (7.1%)
Flushing
6
6 (7.1%)
Anorexia
4
Confusional state
6
24 (28.2%)
9 (10.6%)
1
8 (9.4%)
8 (9.4%)
2
8 (9.4%)
2
6 (7.1%)
6 (7.1%)
6 (7.1%)
* Adverse events included in this table were collected for 42 days from any treatment with laromustine
(following first and/or second induction cycle).
20
Table 5 Response by risk group and by number of baseline risk factors
N
CR/CRp
Overall
Response Rate
Age ≥ 70
66
17/4
32%
ECOG PS = 2
35
7/4
31%
Unfavorable Cytogenetics
40
6/2
20%
Pulmonary Dysfunction
65
14/7
32%
Cardiac Dysfunction
62
14/7
34%
Hepatic Dysfunction
3
0/0
0%
1-2
21
8/0
38%
≥3
64
12/7
30%
Total
85
20/7
32%
Risk Factors
Number of risk factors
21
Figure 1. Overall survival: All patients versus responding (---) patients
22
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