Autologous stem cell ovarian transplantation to increase reproductive potential in patients who are poor responders

Abstract Study question Does autologous bone marrow derived stem cell (BMDSC) ovarian transplantation optimize ovarian reserve parameters in young infertile women with diminished ovarian reserve (DOR) ? Summary answer The autologous stem cell ovarian transplantation (ASCOT) improves AFC and AMH by facilitating the recruitment of existing dormant follicles in young women with DOR. What is known already Oocyte donation is the practical therapeutic option when patients with premature ovarian ageing desire pregnancy. It involves significant psychological burden in terms of not able to have their own biological child. ASCOT has opened new doors in poor responders and premature ovarian insufficiency through its beneficial effects on ovarian reserve and IVF outcomes. However recent studies have shown contradictory results in terms of its efficacy. No prior study has been contemplated in DOR group Study design, size, duration An open label non randomized controlled trial was conducted at Division of Reproductive Medicine in collaboration with stem cell facility at tertiary care institute. Forty two infertile women less than 35 years age with DOR (AFC<5, AMH<1.2ng/ml and /or high FSH>8IU/l) were enrolled in the study during a period from January 2020 to December 2020. 20 women who did not opt for the intervention were treated as control group whereas 22 women received the intervention. Participants/materials, setting, methods Baseline hormonal profile ( Day 2 FSH, estradiol, AMH and AFC) was done in all patients. Women with abnormal uterine cavity, endometriosis, prior ovarian surgery, abnormal karyotype were excluded. Bone marrow aspiration followed by mesenchymal stem cells isolation was performed. The stem cells were transplanted in both the ovaries through transvaginal route on the same day. Follow up visits were planned at one and six months to assess ovarian reserve parameters. Main results and the role of chance The mean age, BMI and duration of infertility were comparable between the control and study group (29.5±3.34vs 29.36±2.95years, 21.51±1.40vs21.87±1.93kg/m2, 6.9±1.94vs7.04±3.67 years). The positive response in terms of improved AMH and AFC was seen in 68% (15/22) patients. The mean number of stem cells injected in these women were 77.71±25.33 million. At first follow up, there was no significant difference between mean FSH, estradiol levels and mean right and left ovarian volume (9.23±3.95 vs 9.02±3.92mIU/l, 61.46±29.25 vs 68.12±62.52 pg/ml, 2.82±2.18 vs 2.44±1.25 cc, 2.02±1.54 vs 2.72±1.06 cc, p < 0.05). There was significant increase in AMH and AFC values as compared to baseline (0.79±0.43 vs 1.26±0.82ng/ml, p = 0.03; 3.47±1.30 vs 6.40±2.23, p < 0.001). At second follow up visit, the significant increase in ovarian reserve persisted for AMH and AFC (0.79±0.43 vs 1.22±0.76 ng/ml, p = 0.02; 3.47±1.30 vs 6.93±1.71,p<0.001). There was no significant difference between serum FSH, Estradiol and ovarian volume. None of the patients developed any complication and the improvement in AFC and AMH persisted during 10 month follow up period. Limitations, reasons for caution The limitation of present study is small sample size and non randomization. However, time period for which positive effect lasts has not been documented in earlier studies. This study is currently being endeavored, and women with improved ovarian reserve are followed up for any spontaneous conception or following assisted reproduction. Wider implications of the findings The present study demonstrates beneficial role of stem cells in improving ovarian reserve parameters in women with DOR with no acquired cause. If supported by future randomized clinical studies, it could represent a paradigm shift for fertility treatment in these women providing an opportunity to have their own biological child Trial registration number CTRI/2020/01/022726

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Spontaneous conceptions and live birth after heterotopic ovarian transplantation: is there a germline stem cell connection?

Human Reproduction ◽

10.1093/humrep/del007 ◽

2006 ◽

Vol 21 (6) ◽

pp. 1345-1348 ◽

Cited By ~ 86

Author(s):

Kutluk Oktay

Keyword(s):

Stem Cell ◽

Live Birth ◽

Germline Stem Cell ◽

Ovarian Transplantation

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Immunological Reconstitution after Autologous Hematopoietic Stem Cell Transplantation in Patients with Systemic Sclerosis: Relationship Between Clinical Benefits and Intensity of Immunosuppression

The Journal of Rheumatology ◽

10.3899/jrheum.081025 ◽

2009 ◽

Vol 36 (6) ◽

pp. 1240-1248 ◽

Cited By ~ 16

Author(s):

TOSHIYUKI BOHGAKI ◽

TATSUYA ATSUMI ◽

MIYUKI BOHGAKI ◽

AKIRA FURUSAKI ◽

MAKOTO KONDO ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Systemic Sclerosis ◽

Clinical Response ◽

Poor Responders ◽

Hematopoietic Stem ◽

Thymic Function ◽

Clinical Benefits ◽

Immunological Reconstitution ◽

Autologous Hsct

Objective.To analyze the relationship between clinical benefits and immunological changes in patients with systemic sclerosis (SSc) treated with autologous hematopoietic stem cell transplantation (HSCT).Methods.Ten patients with SSc were treated with high-dose cyclophosphamide followed by highly purified CD34+ cells (n = 5) or unpurified grafts (n = 5). Two groups of patients were retrospectively constituted based on their clinical response (good responders, n = 7; and poor responders, n = 3). As well as clinical findings, immunological reconstitution through autologous HSCT was assessed by fluorescence-activated cell sorter analysis, quantification of signal joint T cell receptor rearrangement excision circles (sjTREC), reflecting the thymic function, andfoxp3, a key gene of regulatory T cells, mRNA levels.Results.Patients’ clinical and immunological findings were similar between good and poor responders, or CD34-purified and unpurified groups at inclusion. The sjTREC values were significantly suppressed at 3 months after autologous HSCT in good responders compared with poor responders (p = 0.0152). Reconstitution of CD4+CD45RO− naive T cells was delayed in good responders compared with poor responders. The phenotype of other lymphocytes, cytokine production in T cells, andfoxp3gene expression levels after autologous HSCT did not correlate with clinical response in good or poor responders. Clinical and immunological findings after autologous HSCT were similar between CD34-purified and unpurified groups.Conclusion.Our results suggest that immunosuppression intensity, sufficient to induce transient suppression of thymic function, is attributable to the feasible clinical response in patients with SSc treated with autologous HSCT. Appropriate monitoring of sjTREC values may predict clinical benefits in transplanted SSc patients after autologous HSCT.

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Chemotherapy-based stem cell mobilization in multiple myeloma patients treated with novel agents: The Mayo Clinic experience.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20000 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20000-e20000

Author(s):

Iuliana Vaxman ◽

Eli Muchtar ◽

Prashant Kapoor ◽

Shaji Kumar ◽

Angela Dispenzieri ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Mayo Clinic ◽

Unmet Need ◽

Poor Response ◽

Novel Agents ◽

Poor Responders ◽

On Demand ◽

Time Period ◽

Cell Mobilization

e20000 Background: In the novel agents’ era, refractoriness to induction in Multiple Myeloma (MM) is relatively rare. This population remain an unmet need and are often excluded from clinical trials. In the current era, chemotherapy-induced stem cell collections are used at Mayo Clinic in “poor responders” to induction, such as patients that progress prior to ASCT or patients with significant disease burden after induction. Methods: This is a retrospective study that includes all MM patients the underwent chemo-mobilization between January 2012 and September 2020 at Mayo Clinic. We compared our cohort to a cohort of 125 matched patients that were transplanted over the same time period and underwent mobilization with G-CSF and “on-demand” plerixafor. We matched the cohorts by level of response by IMWG at pre-transplant evaluation. Results: 125 newly diagnosed MM patients who received novel agents’ induction and had a poor response to induction were mobilized using IV intermediate-dose cyclophosphamide (83%) or VDT-PACE (17%) plus G-CSF and “on-demand” plerixafor. The median PFS and OS of the chemo-mobilized cohort were 16 months (95% CI 11-20) and 47 months (95% CI 37-71), respectively. Patients receiving chemo-mobilization had higher stem cell yields than the growth factor only cohort (median 9.88X106 cells/kg versus median 8.77X106 cells/kg, respectively (P<0.001)). The safety profile of chemo-mobilization was favorable, with no difference between the two groups in length of hospitalization during ASCT (P=0.95), days to neutrophil or platelet engraftment, and risk of bacteremia (P=0.38). 29% of the chemo-mobilized cohort and 66% of the matched cohort required plerixafor for adequate mobilization (P<0.001). Conclusions: Chemo-mobilization enhances stem cell collection in MM patients with a suboptimal response to induction and reduces the need for plerixafor without adversely impacting the post-transplant clinical course. [Table: see text]

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P–796 Trial of Autologous Marrow derived Stem Cell Ovarian Transplantation (TAMSCOT) in young infertile women with diminished ovarian reserve for ovarian rejuvenation – HOPE still persists

Human Reproduction ◽

10.1093/humrep/deab130.795 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

N Singh ◽

Y Dogra ◽

S Mohanty ◽

T Seth

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Ovarian Reserve ◽

Ovarian Volume ◽

Ovarian Transplantation ◽

Infertile Women ◽

Significant Difference ◽

The Mean

Abstract Study question Does autologous bone marrow derived stem cell (BMDSC) ovarian transplantation optimize ovarian reserve parameters in young infertile women with diminished ovarian reserve (DOR) ? Summary answer The autologous stem cell ovarian transplantation (ASCOT) improves AFC and AMH by facilitating the recruitment of existing dormant follicles in young women with DOR. What is known already Oocyte donation is the practical therapeutic option when patients with premature ovarian ageing desire pregnancy. It involves significant psychological burden in terms of not able to have their own biological child. ASCOT has opened new doors in poor responders and premature ovarian insufficiency through its beneficial effects on ovarian reserve and IVF outcomes. However recent studies have shown contradictory results in terms of its efficacy. No prior study has been contemplated in DOR group Study design, size, duration An open label non randomized controlled trial was conducted at Division of Reproductive Medicine in collaboration with stem cell facility at tertiary care institute. Forty two infertile women less than 35 years age with DOR (AFC<5, AMH<1.2ng/ml and /or high FSH>8IU/l) were enrolled in the study during a period from January 2020 to December 2020. 20 women who did not opt for the intervention were treated as control group whereas 22 women received the intervention. Participants/materials, setting, methods Baseline hormonal profile ( Day 2 FSH, estradiol, AMH and AFC) was done in all patients. Women with abnormal uterine cavity, endometriosis, prior ovarian surgery, abnormal karyotype were excluded. Bone marrow aspiration followed by mesenchymal stem cells isolation was performed. The stem cells were transplanted in both the ovaries through transvaginal route on the same day. Follow up visits were planned at one and six months to assess ovarian reserve parameters. Main results and the role of chance The mean age, BMI and duration of infertility were comparable between the control and study group (29.5±3.34vs29.36±2.95years, 21.51±1.40vs21.87±1.93kg/m2, 6.9±1.94vs7. 04±3.67 years) . The positive response in terms of improved AMH and AFC was seen in 68% (15/22) patients. The mean number of stem cells injected in these women were 77.71±25.33 million. At first follow up, there was no significant difference between mean FSH, estradiol levels and mean right and left ovarian volume (9.23±3.95 vs 9.02±3.92mIU/l, 61.46±29.25 vs 68.12±62.52 pg/ml, 2.82±2.18 vs 2.44±1.25 cc, 2.02±1.54 vs 2.72±1.06 cc, p < 0.05). There was significant increase in AMH and AFC values as compared to baseline (0.79±0.43 vs 1.26±0.82ng/ml, p = 0.03; 3.47±1.30 vs 6.40±2.23, p < 0.001). At second follow up visit, the significant increase in ovarian reserve persisted for AMH and AFC (0.79±0.43 vs 1.22±0.76 ng/ml, p = 0.02; 3.47±1.30 vs 6.93±1.71,p<0.001). There was no significant difference between serum FSH , Estradiol and ovarian volume. None of the patients developed any complication and the improvement in AFC and AMH persisted during 10 month follow up period. Limitations, reasons for caution The limitation of present study is small sample size and non randomization. However, time period for which positive effect lasts has not been documented in earlier studies. This study is currently being endeavored, and women with improved ovarian reserve are followed up for any spontaneous conception or following assisted reproduction. Wider implications of the findings: The present study demonstrates beneficial role of stem cells in improving ovarian reserve parameters in women with DOR with no acquired cause. If supported by future randomized clinical studies, it could represent a paradigm shift for fertility treatment in these women providing an opportunity to have their own biological child. Trial registration number CTRI/2020/01/022726

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GvATLL Effect in the Relapse and Progression Cases After Hematopoietic Stem Cell Transplantation (HSCT) for Adult T-Cell Leukemia/Lymphoma (ATLL).

Blood ◽

10.1182/blood.v114.22.4299.4299 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4299-4299

Author(s):

Nobuaki Nakano ◽

Ayumu Kubota ◽

Mayumi Tokunaga ◽

Masahito Tokunaga ◽

Shogo Takeuchi ◽

...

Keyword(s):

Stem Cell ◽

Skin Lesion ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Poor Responders ◽

Cell Leukemia ◽

Term Survival ◽

Adult T Cell Leukemia

Abstract Abstract 4299 Background Adult T-cell leukemia/lymphoma (ATLL) has a poor prognosis because of its chemo-resistance. Many chemotherapeutic regimens have been created but none of them have shown sufficient results. We proposed allogeneic stem cell transplantation (allo-SCT) for ATLL patients and showed an improved survival rate. However, relapse or progression of ATLL is one of the major limiting factors of survival in post SCT patients. Aims In order to establish a better treatment strategy for poor responders after SCT for ATLL, we analyzed the outcome of relapse or progression cases after allo-SCT. We paid special attention to the graft versus ATLL (GvATLL) effect. Methods There were 37 ATLL patients in which allo-SCT was performed in Imamura Bun-in Hospital (IBH) from June 1998 to April 2009. Twenty-eight cases survived over 100 days after SCT. Sixteen of the 30 patients relapsed. Using data in medical records of IBH, we analyzed transplant characteristics and the outcome of these 17 patients retrospectively. Results Disease status at SCT was CR in 2 patients, 2 PR, 5 SD, and 7 PD. Eight patients received conventional stem cell transplantation (CST) and the other seven patients received reduced-intensity stem cell transplantation (RIST). Fourteen patients in 17 obtained remission (10 CR and 5 PR), but the remaining 2 did not (1 SD and 1 PD) after SCT. The sites of relapse or progression in 17 were skin in 10 patients, 8 peripheral blood, 7 lymph node, 3 central nervous system, and 1 bone. All patients discontinued immunosuppressants after relapse or progression. Eleven patients obtained remission. Especially, in 5 out of 11 patients, remission was obtained only by discontinuation of immunosuppressants (graft-versus-ATLL effect), and the time to remission after discontinuation of immunosuppressants was between 1 to 14 days. Twelve patients were complicated with acute GVHD (grade I-IV). Twelve patients died after SCT. The causes of death were disease progression of ATLL in 5 patients, 3 acute GvHD, 3 infectious complications, and 1 interstitial pneumonia. Four patients who were complicated with acute GvHD survived over 3 years. Discussions Ten patients out of 17 experienced relapse or progression as skin lesion, and 8 patients out of 10 achieved re-remission. It suggests that skin lesion can be a warning sign of ATLL relapse. Since various types of clinical entities, such as ATLL relapse, GvHD, or drug eruption, can manifest as skin lesion after SCT, we strongly recommend to do skin biopsy aggressively to clarify the diagnosis. Ten patients out of 17 achieved re-remission (5 of them achieved only after the discontinuation of immunosuppressant), and 2 patients out of 5 attained long-term survival. This fact raises the possibility that GvATLL effect play a role in controlling exacerbation of ATLL. By focusing on the 5 cases that obtained re-remission only with discontinuation of immunosuppressant, 4 cases showed GvATLL effect prior to GvHD, and one patient experienced fatal grade IV GvHD, respectively. These outcomes suggest that immunosuppressant should be resumed in response to the signs of GvHD deterioration. Relapse/progression cases shows poor survival rate compared with non-relapse ones (60% vs 20% P=0.0028). Although re-remission was highly achieved, this fact suggested that countermeasure against GvHD or re-relapse are indispensable for long-term survival. Summary/conclusions Skin was a major site of relapse or progression after SCT in ATLL patients. A certain number of patients obtained remission only by the discontinuation of immunosuppressants. Four patients survived more than 3 years with their complication of acute GVHD. These results suggest that the GvATLL effect after SCT exists and plays an important role in longer survival for poor responders of post allo-SCT in ATLL patients. Disclosures: No relevant conflicts of interest to declare.

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Non-metastatic Ewing's family tumors: High-dose chemotherapy with stem cell rescue in poor responder patients. Preliminary results of the Italian/Scandinavian ISG/SSG III protocol

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10014 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10014-10014 ◽

Cited By ~ 5

Author(s):

S. Ferrari ◽

T. Alvegard ◽

R. Luksch ◽

A. Tienghi ◽

K. S. Hall ◽

...

Keyword(s):

Stem Cell ◽

Poor Response ◽

High Dose Chemotherapy ◽

Induction Treatment ◽

Poor Responders ◽

High Dose ◽

Event Free Survival ◽

Free Survival ◽

Stem Cell Rescue

10014 Background: Poor response to induction chemotherapy negatively affects prognosis for Ewing's sarcoma (ES) patients. To improve outcome, high-dose chemotherapy (HDCT) with stem cell rescue was added to conventional chemotherapy in patients poor responders after induction treatment. Methods: Non-metastatic ES patients aged <= 40 years were eligible. All patients received VAC (vincristin 2 mg-doxorubicin 80 mg/m2-cyclofosfamide 1,200 mg/m2) weeks 0 and 6, IVAc (ifosfamide 9g/m2-vincristin 2 mg-actinomycin 2 mg) week 3 and IE (ifosfamide 9g/m2-etoposide 450 mg/m2) week 9 as induction therapy. Poor response was histologically defined as persistence of microfoci of viable tumor cells and radiologically as persistence of soft tissue mass. As maintenance treatment good responders (GR) received three cycles of VAC-IVAc-IE. Poor responders (PR) received VAC (weeks 13,19), IE (week 22), CE (mobilizing cycle, cyclophoshamide 4g/m2, etoposide 600 mg/m2, week 16) and HDCT with BuMel (busulfan 4 mg/kg × 4 days orally and melphalan 140 mg/m2 with stem cell support week 25). Results: Starting from 1999, 296 patients were enrolled with a median age of 15 years (3–40). 54 % of the tumors were located to the extremities and 46% in the axial skeleton. 274 patients underwent local treatment: surgery in 222 (81%) patients (with post operative Rxt in 70), RxT alone in 52 (19%). 10 patients progressed during treatment. No toxic deaths were recorded. Response evalutation was available for 262 patients: 135 (52%) were PR. 116 of them completed protocol treatment and 19 did not receive HDCT (5 poor harvest, 5 medical contraindication, 9 refusal).With a median follow-up of 37 months (1–89) 5-year overall and event-free survival were 74 % and 65.5% respectively. 5-year event-free survival was 71% (95% CI 62–81%) for GR, 68% (95% CI 58–78%) for PR treated with HDCT and 35% (95% CI 10–60%) for PR who did not receive HDCT. Conclusions: The preliminary survival data show for PR similar outcome as for GR. The treatment including HDCT is feasible with no toxic death recorded. Longer follow-up will confirm its efficacy. No significant financial relationships to disclose.

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