We read with interest the paper by Rovo et al,1 who studied spermatogenesis in 39 long-term survivors after allogeneic stem cell transplantation (allo-SCT). Eleven patients had recovery of spermatogenesis. The authors found that a younger age (<25 years) and a non–total-body irradiation (TBI)–based conditioning regimen (CR) were independent factors predicting active sperm production after allo-SCT.
At our institution, male patients gave written consent to be enrolled in a long-term posttransplantation follow-up study, including annual semen analysis (SA). Of the 74 patients enrolled in the study, 40 were male, and 35 underwent a SA. The indication for allo-SCT was chronic myelogenous leukemia (CML; 25 patients), myelodysplastic syndrome (MDS; 5 patients), acute myelogenous leukemia (AML; 3 patients), acute lymphoblastic leukemia (ALL; 1 patient), and chronic lymphocytic leukemia (CLL; 1 patient). Median follow-up after transplantation was 6 years (range, 3-13 years). Most (33) patients (median age, 38 years; range, 17-56 years) received a fractionated TBI (12-13.6 Gy)–based myeloablative stem cell transplantation (MST); 2 patients (aged 39 and 40 years) received a non-TBI nonmyeloablative stem cell transplantation (NST). Follicle-stimulating hormone (FSH) levels ranged from 6 to 46 U/L (median, 19 U/L; reference range, 2-15 U/L), and free testosterone levels ranged from 0.18738 to 0.82586 μM (5.4-23.8 ng/dL) (median, 0.449365 μM [12.95 ng/dL]; reference range, 0.3123-1.041 μM [9-30 ng/dL]) in all patients except for 1, who was treated with a testosterone patch. SA and morphology were assessed as described previously.1,2 Five (14.3%) patients showed evidence of sperm production (3 [9%] MST recipients and the 2 NST recipients; Table 1). Sperm production was associated with younger age at transplantation (≤ 30 years old; P = .04), and a follow-up of 7 years or more (3 of 5 vs 0 of 28; P = .002) in MST recipients. Both NST recipients had spermatogenesis and the highest sperm counts, despite their older age. We did not find a relationship with disease type (P = .874), acute graft-versus-host disease (aGVHD; P = .371), or chronic GVHD (cGVHD; P = .600). In fact, all 5 patients with sperm production had developed cGVHD at some timepoint after transplantation. We also found no relationship between FSH and testosterone levels and spermatogenesis. Mouse models suggest that Leydig cells (producing testosterone) may be a target for GVHD,3 but normal testosterone levels in all but 1 patient suggests that Leydig cells were not a target of cGVHD in these patients. Our data therefore confirm those of the Basel group1 and emphasize that male fertility is seriously compromised by TBI, with delayed recovery only possible in younger transplant recipients. Furthermore, it should be noted that only the recipients of NST had near-normal sperm counts, and that no patient has yet proven to be fertile. The most practical approach to preserving fertility after transplantation, therefore, appears to be the use of non-TBI–based regimens or sperm-banking prior to TBI when possible. It remains to be determined whether intracytoplasmic sperm injection (ICSI) techniques might permit fertilization in individuals with low but detectible motile sperm after transplantation.4 In summary, unless more encouraging data are forthcoming with longer follow-up, male patients receiving TBI-based preparative regimens should be advised that return of fertility after transplantation is most unlikely.
Details of patients with evidence of spermatogenesis
. | . | . | . | . | . | . | . | . | Semen analysis . | . | . | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient no. . | Diagnosis . | Age at SCT, y . | Conditioning regimen . | Follow-up, y . | aGVHD, grade . | cGVHD, L or E . | FSH, 1-15 U/L* . | Free testosterone, 0.3123-1.041 μM* . | Concentration, >20 × 106/mL* . | % motile, >50%* . | % normal morphology, >14%* . | ||
| 1 | MDS | 29 | TBI, Cy, Flu | 7.1 | 0 | L | 17 | 0.54826 | <1† | 76* | <1† | ||
| 2 | CML | 20 | TBI, Cy | 9.8 | 0 | L | 11 | 0.57949 | 9.3 | 48 | 12 | ||
| 3 | CML | 30 | TBI, Cy | 12.3 | 0 | L | 23 | 0.4164 | 2.7 | 85 | 6.9 | ||
| 4 | CML | 39 | Cy, Flu | 7.8 | II | E | 4 | 0.51009 | 39 | 69 | 54 | ||
| 5 | CML | 40 | Cy, Flu | 5.6 | II | L | 5 | 0.25331 | 11 | 78 | 21 | ||
. | . | . | . | . | . | . | . | . | Semen analysis . | . | . | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient no. . | Diagnosis . | Age at SCT, y . | Conditioning regimen . | Follow-up, y . | aGVHD, grade . | cGVHD, L or E . | FSH, 1-15 U/L* . | Free testosterone, 0.3123-1.041 μM* . | Concentration, >20 × 106/mL* . | % motile, >50%* . | % normal morphology, >14%* . | ||
| 1 | MDS | 29 | TBI, Cy, Flu | 7.1 | 0 | L | 17 | 0.54826 | <1† | 76* | <1† | ||
| 2 | CML | 20 | TBI, Cy | 9.8 | 0 | L | 11 | 0.57949 | 9.3 | 48 | 12 | ||
| 3 | CML | 30 | TBI, Cy | 12.3 | 0 | L | 23 | 0.4164 | 2.7 | 85 | 6.9 | ||
| 4 | CML | 39 | Cy, Flu | 7.8 | II | E | 4 | 0.51009 | 39 | 69 | 54 | ||
| 5 | CML | 40 | Cy, Flu | 5.6 | II | L | 5 | 0.25331 | 11 | 78 | 21 | ||
L indicates limited; E, extensive; Cy, cyclophosphamide; and Flu, fludarabine.
Normal range.
Out of 198 fields read, 17 sperm were seen, of which 13 were motile (76% motility).
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Definition of prognostic factors: can the return of spermatogenesis after allogeneic HSCT now be predicted?
Gonadal dysfunction and infertility are of major concern in long-term survivors after allogeneic hemopoietic stem cell transplantation (HSCT); several publications have addressed this particular question by trying to identify prognostic factors.1-4 Despite differences in the patient cohorts, the data presented by the National Institutes of Health (NIH) group in this issue of Blood provide similar results to our recent publication.5 This confirms that return of spermatogenesis is associated with young age at transplantation and long follow-up, even in patients conditioned with myeloablative regimens that included TBI.
Savani et al reported sperm production in 5 of 35 male patients after HSCT. From 33 patients conditioned with TBI, 3 showed sperm in their seminal fluid after HSCT. Two patients conditioned with a reduced-intensity regimen had spermatogenesis recovery during their follow-up as well. The authors compared their experience with the results published by the Basel group. The median age of the NIH patients at time of transplantation was older (38 years; range, 17-56 years vs 25 years; range, 5-56 years for the Basel group), and follow-up time was shorter (6 years; range, 3-13 years vs 9 years, range, 2-20 years). Both publications demonstrated that a younger age at transplantation (Savani et al, ≤ 30 years; Basel group, ≤ 25 years) and longer follow-up (≥ 7 years and ≥ 9 years, respectively) are prognostic factors for spermatogenesis recovery. The lower rate of recovery observed by Savani et al (14.3%) compared with the Basel group (28%) could be explained by the older age and a shorter follow-up.
Reduced-intensity conditioning should not be considered a synonym for fertility recovery, since the return of spermatogenesis also depends strongly on the treatment received before transplantation. For instance, most patients receiving allogeneic HSCT for multiple myeloma or lymphoma are often heavily pretreated with or without autologous HSCT, whereas patients with CML are not. So far, there are no data available on the long-term survivorship of patients conditioned with reduced-intensity modality; therefore, prospective studies should be conducted to address this particular issue.
The role of chronic graft-versus-host disease (cGVHD) as alloimmune-mediated damage of gonadal tissue remains an open question, since neither of the studies brought enough evidence for further conclusion. In our cohort, within all patients with some degree of spermatogenesis only 2 had mild cGVHD, and none had a severe presentation. There was statistically a trend in favor of the return of spermatogenesis in patients without chronic GVHD;5 thus, these data suggest that gonadal harm might be determined by extension and severity of cGVHD.
In conclusion, both studies remind us that spermatogenesis and fertility are seriously impaired after allogeneic HSCT. However, the current identification of prognostic factors allow for the prediction of the return of sperm production and gives some hope for prospective follow-up of male long-term survivors after allogeneic HSCT. Potential fertility and the related requirement of birth control counseling become an essential matter to be systematically discussed with the long-term survivors.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Alicia Rovó, Division of Hematology, University Hospital, Basel, Petersgraben 4, CH-4031 Basel, Switzerland; e-mail: rovoa@uhbs.ch.
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