Original Study

Impact of Reduced-Intensity Conditioning

Allogeneic Stem Cell Transplantation on
Women’s Fertility
Emmanuelle Assouline,1 Roberto Crocchiolo,2 Thomas Prebet,2
Florence Broussais,2 Diane Coso,2 Marc Gamerre,3 Norbert Vey,2 Didier Blaise,2
Blandine Courbiere3,4
Abstract
Allogeneic stem cell transplantation (Allo-SCT) after myeloablative conditioning causes premature ovarian
failure (POF) in 95% to 100% of cases. We showed that despite the use of a reduced intensity conditioning (RIC)
regimen, most patients (86.3%) had POF. Our data showed that after RIC Allo-SCT fertility seems to depend on
previous cumulative doses of chemotherapeutic agents.
Introduction: Available data on women fertility for younger patients treated using RIC Allo-SCT are still limited. We
evaluated ovarian function and fertility among female patients younger than 35 years who received RIC Allo-SCT for
hematological malignancy or aplastic anemia (AA). Patients and Methods: Information on therapies before RIC Allo-
SCT were collected. Data on ovarian function and fertility evaluation after RIC Allo-SCT included clinical and biological
criteria. Twenty-two patients were evaluated. Results: After RIC Allo-SCT, amenorrhea affects 68.1% of patients.
Ovarian function was impaired for 86.3% of cases. All 3 AA patients have regular cycles and became pregnant after
RIC Allo-SCT. Only 6 (27.2%) patients declared to have been correctly informed before RIC Allo-SCT on potential
deleterious effects on fertility of anticancer treatment and only 36.8% of patients with ovarian failure had a hormonal
supplementation. Conclusion: Results showed a high rate of ovarian failure, evaluated by clinical and biological
criteria. The difference between AA and malignant diseases might suggest that a potential deleterious role was played
by previous anticancer treatments rather than by RIC Allo-SCT.

Clinical Lymphoma, Myeloma & Leukemia, Vol. 13, No. 6, 704-10 ª 2013 Elsevier Inc. All rights reserved.
Keywords: Allogeneic stem cell transplantation, Chemotherapy, Fertility preservation, Hormone replacement therapy
Premature ovarian failure

Introduction increased worldwide1 and the number of long-term survivors

Allogeneic stem cell transplantation (Allo-SCT) is 1 of the
potential curative options for several hematological diseases and
might represent the only curative approach in some hematological
malignancies. The number of Allo-SCTs has progressively
1
Department of Oncology, Institut Paoli-Calmettes, Marseille, France
2
Department of Hematology, Institut Paoli-Calmettes, Marseille, France
3
Department of Gynecology, Obstetrics, and Reproduction, AP-HM La Conception,
Marseille, France
4
Biogénotoxicologie, Santé Humaine & Environnement UMR 6116, IMBE, Aix-
Marseille, Université, Aix-en-Provence, France
Submitted: Mar 3, 2013; Revised: May 13, 2013; Accepted: May 23, 2013; Epub:
Sep 24, 2013
Address for correspondence: Emmanuelle Assouline, MD, Department of Oncology,
Institut, Paoli-Calmettes, 232 bd Sainte Marguerite, 13273 Marseille Cedex 9, France
Fax: 04-91-22-35-45; e-mail contact: assoulinee@ipc.unicancer.fr
increased in parallel, raising the issue of long-term toxicities. For
instance, intensive chemotherapy and/or radiotherapy used for
conditioning regimens are associated with gonadic toxicity and
might cause premature ovarian failure (POF) in younger patients.2
POF is defined by a premature depletion of ovarian follicles before
the age of 40 years and is characterized by secondary hyper-
gonadotropic amenorrhea. After conventional allogeneic trans-
plantation, rates of POF ranges from 95% to 100%,3,4 and
pregnancy rate is extremely low, ranging from 0.6% to 5.5%
according to the studies.5,6 Over the past 20 years, the use of
reduced intensity conditioning (RIC) Allo-SCT has progressively
increased. This approach is characterized by reduced doses of
chemotherapy and/or radiotherapy, aiming at reducing short-term
toxicities and allowing transplantation in patients for whom
myeloablative conditioning is not feasible. This was mainly

704 - Clinical Lymphoma, Myeloma & Leukemia December 2013

2152-2650/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.clml.2013.05.014
developed for elderly patients but has also been used for younger
patients. Interestingly, there are few data in the RIC Allo-SCT
setting regarding gonadic toxicity in the youngest patients. Ef-
fects of chemotherapy and radiotherapy on ovarian function are
dose-dependent7 and the use of RIC Allo-SCT potentially reduces
ovarian toxicity. The aim of this study was to evaluate ovarian
function and fertility of patients undergoing RIC Allo-SCT, to
better identify patients who are likely to develop POF, and
to better counsel them. We also evaluated the information pro-
vided to patients about infertility risks and fertility preservation
programs.
Patients and Methods
Patient Selection
Patients eligible for the analysis were female, aged 18-35 years,
and treated between January 2000 and January 2010 for hemato-
logical disease at Institut Paoli-Calmettes (Marseille, France) with
RIC or nonmyeloablative Allo-SCT8 and alive at the last follow-up
in August 2011. All patients gave their written informed consent for
participation in the study, which was approved by the local Ethical
Committee. Patients and transplant data were collected using
electronic clinical records: disease, therapy lines before and after
transplantation, conditioning regimen, and relapse after transplant if
applicable. Cumulative doses of cyclophosphamide, melphalan,
busulfan, and radiation were calculated. RIC and nonmyeloablative
conditioning as elsewhere defined8 are referred to as RIC herein.
Transplants were performed using bone marrow, peripheral blood
stem cells, or cord blood as stem cell sources. Donors were related
(human leukocyte antigen-identical sibling) or 10/10-matched un-
related. Prophylaxis against pneumocystis jirovecii and toxoplas-
mosis consisted of trimethoprim-sulfamethoxazol. Amoxicillin,
valacyclovir, and fluconazole were administered as prophylaxis
against encapsulated bacteria, herpes simplex virus, and candida.
Patients were monitored for cytomegalovirus (CMV) reactivation
during the first 6 months after transplant, and preemptive antiviral
therapy was given if CMV reactivation occurred.
Ovarian Reserve Assessment After RIC Allo-SCT and
Fertility Outcome
Data on ovarian function and fertility after RIC Allo-SCT were
collected during gynecological consultation proposed systematically
after the end of cancer treatments: menstrual cycles, and meno-
pausal symptoms. Serum levels of follicle-stimulating hormone
(FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian
hormone (AMH) were measured at day 2 or 3 of the cycle in
patients with spontaneous menses or during amenorrhea in others.
AMH was evaluated to best reflect quantitative ovarian reserve,
because it has been shown that it is more sensitive than LH, FSH, or
estradiol,9 and not affected by menstrual cycle or oral contracep-
tion.10 Biological assessment of ovarian reserve was not performed
in pregnant patients after RIC Allo-SCT. Results are presented as
median with ranges. We evaluated pregnancy rate, term delivery,
mode of delivery, and the health of the child after RIC Allo-SCT.
We also evaluated the prescription of hormone replacement ther-
apy (HRT) or hormonal contraception (HC). Patients were also
asked about impairment of ovarian function information and
fertility preservation techniques received before RIC Allo-SCT.
Results
Patient Characteristics
A total of 96 patients aged 18 to 35 years underwent RIC Allo-
SCT between January 2000 and January 2010. Fifty patients were
alive when the study started, and 23 were female patients selected
for the analysis. One patient was lost to follow-up. Therefore, a total
of 22 patients were included in our study. One patient died after
inclusion because of chronic graft vs. host disease (GvHD). Median
follow-up from RIC Allo-SCT was 50 months (range, 5-93 months).
Median age at last follow-up was 32.5 years (range, 22-46 months);
median age at transplantation was 27 years (range, 18-35 years). Main
patient and transplant characteristics are detailed in Tables 1 and 2.
In 23 patients, 8 patients (36%) were treated for Hodgkin
lymphoma, 5 patients (23%) for acute myeloid leukemia, 3 patients
(14%) for aplastic anemia (AA), 2 patients (9%) for acute lymphoid
leukemia, 2 patients (9%) for multiple myeloma, 1 patient (4.5%)
for non-Hodgkin lymphoma, and 1 patient (4.5%) for chronic
lymphoid leukemia. Except the 3 cases of AA, all patients received
chemotherapy before RIC Allo-SCT: 27% of patients had received
1 previous line of chemotherapy, 32% had received 2 lines, and
27% had received 3 lines or more (Table 1). One had received
subdiaphragmatic radiotherapy. Autologous transplant with BEAM
(carmustine, etoposide, aracytine, and melphalan) conditioning or
high-dose melphalan (140 or 200 mg/m2) was performed in 45.4%
of the patients. A combination of fludarabine 150 to 180 mg/m2
total dose, either oral busulfan 8 mg/kg or intravenous formulation
6.4 mg/kg, and antithymocyte globulin (ATG) 2.5 to 7.5 mg/kg
was administered to 10 patients and fludarabine 200 mg/m2,
cyclophosphamide 50 mg/kg, and total body irradiation (TBI) 2
Gy to 4 patients. Other conditioning regimens were: cyclophos-
phamide 200 mg/kg and ATG 12.5 mg/kg (n ¼ 3), TBI 2 Gy
either alone (n ¼ 1) or in combination with fludarabine 90 mg/m2
(n ¼ 3), or fludarabine and rituximab (n ¼ 1) (Table 1). Cyclo-
sporine alone or in combination with mycophenolate mofetil was
used as GvHD prophylaxis according to local guidelines or pro-
tocols.11 At the time of the study, 77.3% of patients were in per-
sisting remission and 22.7% relapsed with 2 patients treated with
chemotherapy and 2 with immunotherapy. Regarding the gyneco-
logic characteristics of the population, median age of first
menstruation was 13 years. Before any oncological treatment,
86.3% of the patients presented with regular menstrual cycles, and
59% had already been pregnant (Table 2).
Ovarian Reserve Assessment After RIC Allo-SCT and
Fertility Outcome
Fifteen patients (68.1%) were in amenorrhea at last contact.
Eight out of these (53%) were already in amenorrhea because of
POF before RIC Allo-SCT. Seven patients presented spontaneous
menses. Three patients diagnosed with AA continued to have reg-
ular menstrual cycles. Three patients, diagnosed with hematological
malignancy, had irregular menses, reappearing 6 months, 1 year,
and 6 years after Allo-SCT. In 1 patient, menstrual bleedings were
attributed to hematocolpos because of vaginal chronic GvHD.
Among the 15 patients with amenorrhea, 13 presented vasomotor
symptoms with hot flashes. Serum hormonal levels were measured
in 14 out of 19 patients with hematological malignancy. Despite
the presence of spontaneous menstrual cycles in 3 patients, a
Clinical Lymphoma, Myeloma & Leukemia December 2013 - 705
 Reduced-Intensity Conditioning and Fertility
Table 1 Characteristics of Patients Who Underwent Table 2 Gynecological Characteristics of Patients Before
Reduced-Intensity Conditioning Allogeneic Oncology Treatment
Stem Cell Transplantation
Characteristic Patients (n [ 22)
Patients Age at Menarche, Median (Range) 13 (11-15)
Characteristic (n [ 22)
Regularity of the Cycles, n (%)
Current Age, Median (Range), years 32.5 (22-46)
Regular, Every 28-35 d 19 (86.3)
Age at Diagnosis, Median (Range), years 27 (18-35)
Irregular 3 (13.7)
Diagnosis, n (%)
Previous Pregnancies, n (%)
Hodgkin lymphoma 8 (36)
0 9 (40.9)
Acute myeloid leukemia 5 (23)
1 6 (27.2)a
Aplastic anemia 3 (14)
2 5 (22.7)
Acute lymphoid leukemia 2 (9)
3 2 (9)
Multiple myeloma 2 (9)
a
Non-Hodgkin lymphoma 1 (4.5) One patient was pregnant at diagnosis.
Chronic lymphoblastic leukemia 1 (4.5)
Number of Lines of Chemotherapy Before Transplant significant impairment of ovarian function was observed in all pa-
0 3 (14)a tients, with elevated FSH (median 58 IU/L; range, 2.5-114) and
1 6 (27) LH levels (median 43 IU/mL; range, 0.2-89). Median AMH (range,
2 7 (32) 0.1-0.9) value was low, relative to a normal value > 2 ng/mL. Five
3 6 (27)
out of 19 patients with POF were receiving HRT, and 2 patients
Subdiaphragmatic Radiotherapy Before Transplant, n (%) 1 (4.5)
HC. No spontaneous pregnancies occurred after Allo-SCT for he-
matological malignancy: 1 patient with irregular menses and POF
Autograft, n (%) 10 (45.4)
underwent intrauterine insemination, 1 patient asked for child
Autograft Conditioning Regimen
adoption. Three pregnancies were recorded among the 3 patients
BEAM 8
with AA, respectively, at 22 months, 4, and 6 years after RIC Allo-
Melphalan 2
SCT. One patient underwent legal termination of pregnancy and 2
Allograft Conditioning Regimen, n (%)
patients had live births after normal gestations. These 3 patients
Cyclophosphamide, ATG 3 (14)b received the highest cumulative doses of cyclophosphamide (8865,
Fludarabine, busulfan, ATG 10 (45) 6883, and 6331 mg/m2 respectively) before RIC Allo-SCT.
TBI 2 Gy, fludarabine, cyclophosphamide 4 (18)
Fludarabine, TBI 3 (14) Information on POF Risk and Fertility Preservation
Fludarabine, ritux 1 (4.5) Only six (27%) patients declared to have been fully informed of
TBI 1 (4.5) risk of POF and infertility induced by RIC Allo-SCT. Five (23%)
Type of Donor, n (%) and 11 (50%) patients declared respectively having received partial
HLA-identical sibling 15 (68) or no information at all. Fertility preservation had been proposed to
10/10-matched unrelatedc 3 (14) 5 patients during specialized oncofertility consultations. Two pa-
Cord blood 4 (18) tients refused ovarian cryopreservation and 3 asked for fertility
Patients With Relapse After Allogeneic 6 (27) preservation: emergency in vitro fertilization for embryo freezing
Stem Cell Transplantation, n (%) before RIC Allo-SCT was performed in 2 patients, with 8 embryos
Lines of Chemotherapy After Relapse, n (%) cryopreserved in one patient and cancellation of the cycle because
1 3 (14) of an absence of follicular response to ovarian stimulation in the
2 1 (4.5) other. The third patient underwent ovarian tissue cryopreservation
3 1 (4.5) before RIC Allo-SCT but she died after inclusion in the present
GvHD, n (%) study, because of Allo-SCT complications. The main gynecological
None 13 (59) and oncology characteristics of the patients and the main results
Chronic 11 (41) of the study are summarized in Table 3.
Current State, n (%)
Relapse 5 (22.7)
Discussion
We report the first study specifically addressed to ovarian func-
Remission 17 (77.3)
tion and female fertility after RIC Allo-SCT based on clinical and
Median follow-up since the allograft (range), mo 50.3 (5-93)
biological criteria, using AMH measurements. We found that
Abbreviations: ATG ¼ anti-thymocyte globulin; BEAM ¼ carmustine, etoposide, aracytine, despite the use of an RIC regimen, most of the patients (86.3%)
melphalan; GvHD ¼ graft vs. host disease; HLA ¼ human leukocyte antigen; TBI ¼ total body
irradiation.
had POF. Only the 3 patients with AA were pregnant after RIC
a
The 3 patients who did not receive previous chemotherapy were patients who received Allo-SCT, stressing the effect of pretransplant radio/chemotherapy.
a transplant for aplastic anemia.
b
The 3 cases of aplastic anemia.
Our data also showed that most patients believe they do not get
c
Matched at allele level or loci A, B, C, DRB1, DQB1 between patient and donor. enough information about fertility.

706 - Clinical Lymphoma, Myeloma & Leukemia December 2013

 Table 3 Ovarian Function Outcome of Patients with Cumulative Doses of Chemotherapy Agents Before RIC Allo-SCT
Age, TBI Cyclophosphamide, Busulphan, Melphalan, Autologous Lines of Follow- Conditioning Menstrual FSH, LH, E2 , AMH,
Patient Pathology years (2 Gy) mg/m2 mg/m2 mg/m2 Transplant Chemotherapy, n Up, mo Regimen Cycle Pregnancy IU/L IU/L mg/mL ng/mL HT Status
1 AA 32 0 8865 0 0 0 0 96 Cy-ATG Regular cycles 1 e e e e 0 Not menopausal
2 AA 24 0 6331 0 0 0 0 76 Cy-ATG Regular cycles 2 e e e e 0 Not menopausal
3 AA 22 0 6883 0 0 0 0 273 Cy-ATG Regular cycles 1 e e e e 0 Not menopausal
4a HL 29 0 0 0 140 0 2 54 Flu-Bu-ATG Amenorrhea 0 93 36 51 0.1 0 POF
5 HL 27 Yes 0 0 140 Yes 2 44 Flu-TBI Amenorrhea 0 114 60 < 25 0.4 0 POF
6 HL 23 Yes 0 0 140 Yes 5 47 Flu-TBI Amenorrhea 0 104 82 9 0.5 0 POF
7 HL 33 Yes 0 0 140 Yes 3 31 Flu-TBI Amenorrhea 0 89 63 28 0.3 0 POF
8b HL 29 0 262 141 0 Yes 2 20 Flu-Bu-ATG Amenorrhea 0 48 47 24 0.3 HRT POF
9c HL 29 Yes 1548 0 0 Yes 4 15 Flu-Cy-TBI 200 Amenorrhea 0 46 40 90 0.7 HRT POF
10 HL 26 0 6000 380 140 Yes 3 12 Flu-Bu-ATG Amenorrhea 0 U U U U 0 POF
11 HL 37 0 0 0 140 Yes 2 70 Flu-Bu-ATG Amenorrhea 0 U U U U 0 POF
12 AML 34 0 311 0 0 Yes 1 93 Flu-Bu-ATG Irregular cycles 0 99 52 14 0.2 0 POF
(6 years after
recovery)
13 AML 24 0 0 260 0 0 4 10 Flu-Bu-ATG Amenorrhea 0 26 23 19 0.3 0 POF
14 AML 41 0 0 164 0 0 1 83 Flu-Bu-ATG Amenorrhea 0 U U U U HC POF
15 AML 40 Yes 1722 0 0 0 2 45 Flu-Cy-TBI 200 Amenorrhea 0 79 64 67 0.5 HRT POF
16 AML 36 0 Followed earlier e e 0 1 118 Flu-Bu-ATG Amenorrhea 0 U U U U HRT POF
outside institute
17d ALL 29 Yes 1538 0 0 0 1 54 Flu-Cy-TBI200 Irregular cycles 0 20 36 239 0.5 0 POF
(1 year after
recovery)
Clinical Lymphoma, Myeloma & Leukemia December 2013

18 ALL 33 Yes 3488 0 0 0 1 34 Flu-Cy-TBI200 Irregular cycles 0 41 15 33 0.4 0 POF

(6 months after
recovery)
19 MM 46 0 3000 0 200 0 2 110 Flu-Bu-ATG Amenorrhea 0 U U U U U POF

Emmanuelle Assouline et al
20 MM 33 Yes 0 0 140 Yes 2 73 TBI Amenorrhea 0 54 89 14 0.9 0 POF
21 CLL 40 Yes 5087 0 0 Yes 3 60 Flu-Ritux Unknowne 0 18 7 13 0.6 HC POF
22 NHL 35 0 3701 267 0 0 1 5 Flu-Bu-ATG Amenorrhea 0 2.5 0.2 35 0.6 0 POF

Abbreviations: AA ¼ aplastic anemia; ALL ¼ acute lymphoblastic leukemia; Allo-SCT ¼ allogeneic stem cell transplantation; AMH ¼ anti-Müllerian hormone; AML ¼ acute myeloide leukemia; ATG ¼ antithymocyte globulin; Bu ¼ busulfan; CLL ¼ chronic lymphocytic leukemia;
Cy ¼ cyclophosphamide; E2 ¼ estradiol; Flu ¼ fludarabine; FSH ¼ follicle stimulating hormone; HC ¼ hormonal contraception; HL ¼ hodgkin's lymphoma; HRT ¼ hormonal replacement therapy; HT ¼ hormonal therapy; IVF ¼ in vitro fertilization; LH ¼ luteinizing hormone;
MM ¼ multiple myeloma; NHL ¼ non-Hodgkin’s lymphoma; POF ¼ premature ovarian failure; RIC ¼ reduced intensity conditioning; Ritux ¼ rituximab; TBI ¼ total body irradiation; U ¼ unrealized.
a
Patient who underwent preservation fertility with emergency IVF before RIC Allo-SCT (8 embryos cryopreserved).
b
Patient who underwent ovarian cryopreservation before RIC Allo-SCT.
c
Patient who underwent preservation fertility with emergency IVF before RIC Allo-SCT with cancellation of the cycle because of an absence of follicular response to ovarian stimulation.
d
Patient given artificial insemination but did not result in pregnancy.
e
Unknown status: menstrual bleeding using HC.
- 707
 Reduced-Intensity Conditioning and Fertility
After myeloablative conditioning regimen, pregnancy rate is

used a medically assisted procreation

Among the 708 postpubertal women,
0.6% to 5.5% (Table 4).5,6,12 These studies are heterogeneous and

232 patients, of which 30 had

Overall fertility rate of 5.5%, 8%

Overall fertility rate of 0.6% or

of men and 3% of women

do not allow precise evaluation of ovarian function. Indeed, they

4.5% were pregnant

include male and female patients treated with autologous or allo-

Fertility Rate
geneic transplant for malignant or nonmalignant diseases. In addi-
tion, fertility before Allo-SCT and parenthood desire is unknown.
For this reason, results concerning pregnancy rates have to be
interpreted with caution. Moreover, after myeloablative condition-
ing, the rate of POF is very high, from 95% to 100%.3,4
Successful pregnancies were reported in a total of 6 women with
hematological malignancies after RIC Allo-SCT.13-15 Interestingly,
median interval to pregnancy was short (6 months, and 1 and 2 years)
Recovery of Ovarian Function

ovarian function, but no clinical or

puberty, 15.5% regained normal

laboratory result is explained

Among the 708 women after

in patients who received a reduced conditioning regimen vs. 5 to 10

years among patients given myeloablative conditioning. The rate of
ovarian failure after RIC Allo-SCT seems to be much higher in our
Unspecified

Unspecified
Table 4 Main Series Describing Ovarian Function and Fertility After Allogeneic Stem Cell Transplantation with Myeloablative Conditioning

study than reported in other publications.16,17 However, the main

assessment criteria in these studies, was amenorrhea or menstrual
cycle persistence after chemotherapy. This seems to be not sufficient
to evaluate ovarian reserve. In our study, we reported not only clinical
but also biological criteria, including AMH that defines more accu-
rately follicular ovarian reserve.9,10
Our data showed that fertility after RIC Allo-SCT seems to
High-dose cyclophosphamide
Conditioning Regimen

alone or in combination

combination with TBI

combination with TBI

Chemotherapy protocol

Chemotherapy protocol
variable alone or in

variable alone or in

depend on previous cumulative doses of chemotherapeutic agents.

Indeed, 53% of patients affected by malignancy were in amenorrhea
with TBI

before RIC Allo-SCT because of probable preexistent POF. Ten

patients had already been treated with autologous transplant.
Therefore, they underwent 2 intensive conditioning chemotherapy
regimens, which increases risk of POF.5,12 Unfortunately, ovarian
reserve evaluation before RIC Allo-SCT was not available.
Aplastic anemia and

Aplastic anemia and

Aplastic anemia and

Papageorgiou et al, who studied 30 women treated with RIC Allo-

malignanacies

malignanacies
hematological

hematological

hematological
malignancies
Pathology

SCT, using biological and clinical criteria, demonstrated that 26

patients had POF before transplant, because of previous chemo-
therapy. Therefore, the POF rate in these patients treated with
RIC Allo-SCT was 86.7%.15 Recently, Behringer et al found that
FSH, AMH, and inhibin B levels correlated significantly with
therapy intensity (P < .001), in a large group of Hodgkin’s lym-
19,412 Patients who received an autologous

marrow transplant and 378 who received

transplantation (men and women mixed)
241 Patients who received an autologous

an allogeneic stem cell transplantation

marrow transplant and 17,950 who

phoma survivors.18 POF risk is greater when more chemothera-

1326 Postpubertal patients and 196

received an allogeneic stem cell

prepubertal patients (men and

(men and women mixed)

Population Concerned

peutic lines are administered and only patients with AA became

pregnant even if treated with the highest doses of cyclophosphamide
women mixed)

(8865, 6883, and 6331 mg/m2), despite the fact that cyclophos-
phamide is among the most gonadotoxic chemotherapy agents.
Sanders et al6 also reported that postpubertal patients who received
high-dose cyclophosphamide during conditioning were likely to
recover their ovarian function.
Besides the issue of fertility, POF is also associated with estrogen
deprivation that increases the risk of osteoporosis, cardiovascular
disease, and sexual and urinary dysfunction.19 There is neither
Retrospective

Retrospective

Retrospective

official recommendation nor randomized controlled trials about

Study

Abbreviation: TBI ¼ total body irradiation.

HRT in women with POF after transplant. In our study, only

36.8% of patients with POF received HRT; 86.6% of them pre-
sented hot flashes. In a study with 80 patients treated for lymphoma
6

Salooja et al, 20015

Sanders et al, 1996

Carter et al, 200612

or leukemia, 90% of them showed vasomotor disorders after stem

cell transplantation which have been improved from the first cycle
of hormonal supplementation.20
Reference

Hormone replacement therapy improves quality of life in cancer

survivors with POF by reducing menopause symptoms (vasomotor
symptoms, dyspareunia, libido troubles, urinary troubles).20-22

708 - Clinical Lymphoma, Myeloma & Leukemia December 2013


Tauchmanovà et al23 reported about patients who received a
transplant during HRT. Fifty-five percent of the 132 patients
started an estradiol (2 mg daily) and dydrogesterone (10 mg for 14
d/mo) HRT. In the allogeneic setting, HRT reduced all menopause
symptoms except osteoporosis, which requires higher HRT doses.
Osteoporosis in patients who received an allograft is indeed multi-
factorial (POF, corticotherapy, and immunotherapy against GvHD,
nutritional and metabolic deficiency, immunodeficiency). Bone loss
is more significant in patients undergoing premature menopause vs.
patients with naturally occurring menopause.22 Despite lack of
evidence to support HRT for preventing osteoporosis, HRT should
be considered to improve the quality of life of cancer survivors with
POF by reducing menopause symptoms.20,21,23
Use of estrogen supplementation should be done using strict
medical control, in the absence of any contraindication (medical
history of previous thromboembolic disease or hepatitis).
Half of our patients declared not to be informed on effect of
anticancer therapy on their fertility. This is in line with previous
publications24 showing the lack of information about the potential
risk of infertility after cancer treatments. Because the participants
were asked retrospectively about the information they had received
about treatment-induced infertility risks, some memory bias could
have occurred. This can also be partially explained by the lack of
data on fertility after RIC Allo-SCT. Anticancer treatment toxicity
on gonads was long considered of secondary importance, consid-
ering the very poor prognosis of affected patients. The question
of subsequent fertility became an issue with improvements of pa-
tient survival. We need to improve the information and counseling
given to patients about their ovarian function, the probability of
pregnancy after RIC Allo-SCT, and the possibility to preserve
fertility.25 We think that this information needs a specific onco-
fertility consultation in a reproduction medicine center to provide
appropriate information, with discussion about the different options
to attempt to preserve fertility.
Conclusion
The rate of POF after RIC Allo-SCT remains high at 86.3%
probably because of all lines of chemotherapy received previously.
This study is expected to improve the information given to patients
about their ovarian function and their probability of conceiving
after RIC Allo-SCT. Patients with AA seem to have a low risk of
POF and fertility preservation methods seem to be not required in
most cases. In contrast, patients with hematological malignancies
should be informed of POF risk and fertility preservation should
be discussed during oncofertility counseling26 as soon as possible
after diagnosis. Proposal of fertility preservation and HRT to all
young patients who receive an allograft should allow improving
their quality of life after cancer treatment.
Clinical Practice Points
 After conventional allogeneic transplantation, rates of POF
ranges from 95% to 100% and pregnancy rate is extremely low.
 Over the past 20 years, the use of RIC Allo-SCT has progres-
sively increased. The aim of our study was to evaluate ovarian
function and fertility of patients undergoing RIC Allo-SCT.
Emmanuelle Assouline et al
 We showed that despite the use of an RIC regimen, most
patients (86.3%) had POF. Our data showed that after RIC
Allo-SCT, fertility seems to depend on previous cumulative doses
of chemotherapeutic agents.
 Premature ovarian failure risk is greater when more chemother-
apeutic lines are administered and only patients with AA in our
study became pregnant. This study will help to better inform
these young patients about the risk of POF and the possibility of
suitable fertility preservation.
 Patients with AA seem to have a low risk of POF and fertility
preservation methods seem to be not required in most cases. In
contrast, patients with hematological malignancies should be
informed of POF risk and fertility preservation should be dis-
cussed during oncofertility counseling as soon as possible after
diagnosis.
 Hormonal replacement therapy could be suggested to patients
with POF, according to their needs and possible contraindica-
tions, to improve their quality of life.
Acknowledgments
The authors thank the team working at the Hematology
Department and Cellular Therapy Unit at Institut Paoli-Calmettes,
Marseille, France, and at the Department of Gynecology, Obstetric
and Reproduction Department at the hospital La Conception,
Marseille France for their remarkable contribution in care of the
patients and assistance to their families.
Disclosure
The authors have stated that they have no conflicts of interest.
References
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for haematological diseases, solid tumours and immune disorders: current practice
in Europe 2009. Bone Marrow Transplant 2010; 45:219-34.
2. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female
reproduction. Hum Reprod Update 2001; 7:535-43.
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