Long-Term Outcome of Allogeneic Stem Cell Transplantation in Patients with Paroxysmal Nocturnal Hemoglobinuria with or without Aplastic Anemia

Abstract Background: Although recently, Eculizumab, humanized monoclonal antibody directed against complement component C5, has used increasingly for the patients with hemolytic paroxysmal nocturnal hemoglobinuria (PNH), allogeneic stem cell transplantation (allo-SCT) can be curative treatment option especially for PNH patients with combined aplastic anemia (AA). The aim of the present study was to evaluate long-term outcome of allo-SCT in patients with AA/PNH. In addition, patients with classic PNH who underwent allo-SCT in the pre-eculizumab era were also evaluated. Methods: Total of 33 patients with PNH clones underwent allogeneic SCT at our institution between Jan 1998 and Jan 2016. Among them, seven patients had classic PNH and 26 patients with cytopenia had AA/PNH (with bone marrow evidence of a concomitant AA). Results: There were 21 male and 12 female patients with a median age of 34 years (range, 13-56 years). Pre-transplant GPI-AP deficient neutrophils and erythrocytes were 5.6% (0-92) and 21% (0-98.5), respectively. Median white blood cell, absolute neutrophil count, hemoglobin, and platelet at transplant were 2.4×109/L, 0.8×109/L, 7.7 g/dL, and 27×109/L, respectively. Median LDH level was 727 U/L (232-7721 U/L) and 19 (58%) patients had LDH ≥1.5x upper limit of normal. Classic PNH (n=7) and AA/PNH [SAA (n=15), VSAA (n=9), or non-SAA (n=2)] received SCT from HLA-matched sibling (MSD, n=24), unrelated (URD, n=7), or haplo-identical donor (Haplo-SCT, n=2). Since 2003, the conditioning regimen for MSD-SCT was changed from Busulfex (12.8 mg/kg) + cyclophosphamide (CY, 120 mg/kg) to fludarabine (180 mg/m2) + CY (100 mg/kg) + rATG (10 mg/kg). The conditioning regimen for URD-SCT and Haplo-SCT were TBI (800 cGy) + CY (100-120 mg/kg) ± rATG (2.5 mg/kg) and TBI 600cGy + Fludarabine (150 mg/m2) + rATG (5 mg/kg), respectively. After a median follow-up of 57 months (range 6.0-151.3), the 5-year estimated OS rates were 87.9 ± 5.7%. Four patients died of treatment-related mortality (TRM), including acute GVHD (n=1), pneumonia (n = 2), and cerebral hemorrhage (n=1), respectively. Except one patient with early TRM, 32 patients engrafted. Two patients who experienced delayed graft-failure received second transplant and recovered. The cumulative incidence of acute GVHD (≥grade II) and chronic GVHD was 27.3 ± 7.9% and 18.7 ± 7.0%, respectively. Among 25 patients with available follow-up data, PNH clone disappeared at median 3.0 months (range 0.7-45.5) after SCT and reemerging of PNH clones was observed in two patients; one patient showed re-appearance of 2.6% GPI-negative neutrophils at 12 months without PNH symptoms, but disappeared again at 21 months. Another patient suffered from labile graft and received a booster with peripheral blood stem cells. Conclusion: This study showed that long-term transplant outcome in patients with AA/PNH were comparable to that of allogeneic SCT in SAA (the 3-year estimated OS rates were 92.7 and 89 % for MSD-SCT and URD-SCT, respectively) at our institution (ASH Annual Meeting Abstracts 2012;120:4151). Reduced-intensity conditioning regimen was sufficient for the eradication of PNH clone in allogeneic SCT. Therefore, application of allogeneic SCT should be considered in PNH patients with AA in case of availability of well matched donor. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Long-Term Outcome of Allogeneic Stem Cell Transplantation in Patients with Combined Paroxysmal Nocturnal Hemoglobinuria and Aplastic Anemia (AA/PNH syndrome)

Blood ◽

10.1182/blood.v124.21.4398.4398 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4398-4398

Author(s):

Sung-Eun Lee ◽

Young-Woo Jeon ◽

Jae-Ho Yoon ◽

Seung-Hwan Shin ◽

Seung-Ah Yahng ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Aplastic Anemia ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Term Outcome ◽

Long Term Outcome ◽

Pnh Clone

Abstract Background:Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disorder of hematopoietic stem cells characterized by a somatic mutation in the PIG-A gene, encoding the glycosyl phosphatidylinositol (GPI) moiety. PNH clones lack GPI-anchored proteins (GPI-AP) which inhibit the activation and cytolytic functions of complement. Recently, Eculizumab, humanized monoclonal antibody directed against complement component C5, has used increasingly for the patients with hemolytic PNH. However, the patients with PNH clone and bone marrow failure syndrome (i.e. aplastic anemia) should be treated as their predominant clinical manifestation. Allogeneic stem cell transplantation (SCT) can be curative treatment option especially for PNH patients with combined aplastic anemia (AA). The aim of the present study was to evaluate long-term outcome of allogeneic SCT in patients with AA/PNH. Methods: Total of 27 patients with PNH clones underwent allogeneic SCT at our institution between Jan 1998 and Mar 2014. Among them, seven patients had classic PNH and 20 patients with cytopenia had AA/PNH (with bone marrow evidence of a concomitant AA). We analyzed long-term transplant outcomes in 20 patients with AA/PNH. Results: There were 12 male and 8 female patients with a median age of 34 years (range, 13-51 years). The median interval from the diagnosis to transplantation was 8 months (range; 1-201 months). The median transfusions prior to SCT were 33 units (range; 8-208 units). Pre-transplant GPI-AP deficient neutrophils and erythrocytes were 46% (0-99) and 15.6% (0-88), respectively. Median white blood cell, absolute neutrophil count, hemoglobin, and platelet at transplant were 2.3×109/L, 0.7×109/L, 7.9 g/dL, and 21×109/L, respectively. Median LDH level was 714 U/L (range; 273-6499 U/L) and 11 (55%) patients had LDH ≥1.5x upper normal limit. PNH patients with SAA (n=14), VSAA (n=4), or non-SAA (n=2) received SCT from sibling (s) donor (n=15) or unrelated (u) donor (n=5). The conditioning regimen for s-SCT consisted of fludarabine (180 mg/m2) + cyclophosphamide (CY, 100 mg/kg) + ATG (10 mg/kg) (n=11), or busulfex (12.8 mg/kg) + CY (120mg/kg) (n=4). The conditioning regimen for u-SCT was TBI (fractionated, 800 cGy) + CY (100-120 mg/kg) ± ATG (2.5 mg/kg). GVHD prophylaxis consisted of CsA + MTX in s-SCT and FK506 + mini-MTX in u-SCT, respectively. After a median follow-up of 57 months (range 4.7-122.1), the 5-year estimated OS rates were 90.0 ± 6.7%. Two patients died of treatment-related mortality (TRM), including acute GVHD (n=1) and cerebral hemorrhage (n=1), respectively. Except one patient with early TRM, 19 patients engrafted with no secondary graft-failure. The cumulative incidence of acute GVHD (≥grade II) and chronic GVHD was 25.0 ± 1.0% and 26.3 ± 10.4%, respectively. PNH clones disappeared at median 1.8 months (range 0.9-11.9) after SCT and reemerging of PNH clone was not observed in all patients. Conclusion: This study showed that long-term transplant outcome in patients with AA/PNH were comparable to that of allogeneic SCT in SAA (the 3-year estimated OS rates were 92.7 and 89 % for s-SCT and u-SCT, respectively) at our institution (ASH Annual Meeting Abstracts 2012;120:4151). Therefore, application of allogeneic SCT should be considered in PNH patients with AA in case of availability of well matched donor. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Long-term outcome of allogeneic stem cell transplantation in chronic lymphocytic leukemia: analysis after a minimum follow-up of 5 years

Leukemia & Lymphoma ◽

10.1080/10428190802263535 ◽

2008 ◽

Vol 49 (9) ◽

pp. 1724-1730 ◽

Cited By ~ 15

Author(s):

Pankaj Malhotra ◽

William J. Hogan ◽

Mark R. Litzow ◽

Michelle A. Elliott ◽

Dennis A. Gastineau ◽

...

Keyword(s):

Stem Cell ◽

Chronic Lymphocytic Leukemia ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Lymphocytic Leukemia ◽

Term Outcome ◽

Long Term Outcome

Download Full-text

Long-Term Outcome of Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Mycosis Fungoides and Sézary Syndrome: The Milan Experience

Blood ◽

10.1182/blood-2018-99-119708 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4655-4655

Author(s):

Francesco Onida ◽

Giorgia Saporiti ◽

Silvia Alberti Violetti ◽

Elena Tagliaferri ◽

Federica Grifoni ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Median Time ◽

Term Outcome ◽

Hematopoietic Stem ◽

Long Term Outcome ◽

Reduced Intensity

Abstract Introduction: Although a few novel drugs have recently shown promising activity in mycosis fungoides (MF) and Sézary syndrome (SS), prognosis of patients with advanced stages or refractory disease remain poor, with median survival ranging from 1.4 to 3.4 years (Agar NS et al. JCO 2010). In selected patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potential curative strategy. By decreasing transplant-related mortality, reduced intensity (RIC) and nonmyeloablative conditioning (NMA) regimens lead to better outcomes in comparison to myeloablative ones. Here we report long-term outcome of our RIC allo-HSCT experimental program, initiated in 2001. Patients & Methods: As of July 2018, in our Center 40 patients underwent RIC allo-HSCT from HLA-identical sibling (n=16), unrelated donors (UD, n=22 - fully-matched in 10, 1 or 2-mismatch in 12) or haploidentical related donors (n=2). Median age was 52 years (range 19-66). All patients (24 M and 16 F) had stage IIB/IV refractory MF (n=27) or SS (n=13). Median number of previous treatment lines was 6 (range 2-12) while median time from diagnosis to transplantation was 46 months (range 11-264). The source of stem cells has been peripheral blood in 35 patients (87.5%), bone marrow in 4 (10%) and cord blood in 1 (2.5%). Conditioning regimens included FC/TBI200, pentostatin+TBI200, and fludarabine/melphalan in transplants from HLA-identical sibling donor or UD, whereas the TT/Flu/CTX/TBI200 regimen was used in the haploidentical setting. GvHD prophylaxis included CsA/MMF in all patients, with the addition of ATG in cases with UD and post-transplant CTX (50 mg/kg giorni +3 e +4) in haploidentical setting. Results: Full donor chimerism was obtained in 32 out of 37 evaluable patients, in a median time of 2 months (range 1-12). Acute GvHD occurred in 18 patients out of the 32 evaluable (56%), being of grade III-IV in 9 (28%). Chronic GvHD was observed in 10 patients (31%), being extensive in 4 (12%). Of note, the latter were all patients transplanted from HLA-identical sibling (i.e. without ATG). Following transplantation, a complete remission (CR) was achieved in 26 out of the 37 evaluable patients (70%), of whom 4 experienced relapse at +2 (2 pts), +25 and +35 months, respectively. At the last follow-up, 19 patients were alive and 17 (89%) maintained CR after a median follow-up of 80 months (range 4-210). Out of the 11 patients who did not achieve CR, 9 died from progressive disease (median follow-up of 12 months, range 3-31), 1 from a secondary malignancy, while 1 is still alive with disease 62 months after transplant. Transplant-related death occurred in 7 patients (17%), of whom 5 were in CR. In the whole population, the 5-year OS was 52% (95% CI 34-70) [Fig.1] and the 5-year DFS was 43% (95% CI 27-62). However, when MF and SS were analysed separately, 5-yrs DFS were 30% (95% CI 12-51) and 72% (95% CI 38-99), respectively (Fig.2). Apart from diagnosis, outcome appeared to be primarily associated with chemosensitivity and status of disease at transplantation. Conclusions: After a median follow-up longer than 6.5 years, we confirm the efficacy of RIC allo-HSCT as a powerful therapeutic strategy in inducing and maintaining remission in selected patients with chemosensitive advanced-stage CTCL, with results particularly encouraging in SS. Disclosures Cortelezzi: roche: Consultancy; abbvie: Consultancy; novartis: Consultancy; janssen: Consultancy.

Download Full-text

Long-term outcome of HLA-haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion based on an FBCA conditioning regimen for hematologic malignancies

Bone Marrow Transplantation ◽

10.1038/bmt.2015.108 ◽

2015 ◽

Vol 50 (8) ◽

pp. 1092-1097 ◽

Cited By ~ 14

Author(s):

X Lin ◽

Z G Lu ◽

C Y Song ◽

Y X Huang ◽

K Y Guo ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Conditioning Regimen ◽

Hematologic Malignancies ◽

Term Outcome ◽

Hematopoietic Stem ◽

Long Term Outcome

Download Full-text

Allogeneic Hematopoietic Stem-Cell Transplantation in AML and MDS Using Myeloablative Versus Reduced Intensity Conditioning: Long-Term Follow-up.

Blood ◽

10.1182/blood.v112.11.2166.2166 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2166-2166

Author(s):

Avichai Shimoni ◽

Avital Rand ◽

Izhar Hardan ◽

Noga Shem-Tov ◽

Yulia Volchek ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Myeloablative Conditioning ◽

Term Outcome ◽

Long Term Outcome ◽

Relapse Rates ◽

Active Disease

Abstract Allogeneic stem-cell transplantation (SCT) with both myeloablative and reducedintensity conditioning (RIC) is effective therapy in AML and MDS. However, the relative merits of each may differ in different settings and the long-term outcome is less defined. We have previously reported on the role of dose intensity in a group of 112 patients (pts) with AML/MDS given allogeneic SCT with different regimens (Leukemia 2006). We showed that survival was similar with myeloablative conditioning and RIC in pts given SCT in remission, but was inferior in pts given RIC in active disease due to high post transplant relapse rates. We have now updated SCT outcomes with an additional 3-year follow-up in the same cohort, to better predict long-term outcome and confirm that late events did not change the initial conclusions. The study group included 112 consecutive pts with AML/ MDS transplanted over a 5-year period. The median age at SCT was 50 years (18–70). Eighty-five pts had AML (39 secondary) and 17 had MDS (all with excess of blasts). Fiftyeight had active disease at SCT (>10% marrow blasts) and 54 were in remission. The donor was HLA-matched sibling (n=58), 1-ag mismatched related (n=6) and matched-unrelated (n=48). Forty-five pts met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). Sixtyseven pts were considered non-eligible for standard myeloablation due to advanced age (over 55 years for sibling SCT or over 50 years for mismatched or unrelated SCT), extensive prior therapy, organ dysfunction, recent fungal infection or poor performance status. These pts were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The median age of this group was 55 years compared with 42 years in the first group, and a larger proportion had SCT from unrelated donors. With a median follow-up of 5.1 years (3.3–8.6), 45 pts are alive and 67 have died (45 relapse, 22 non-relapse causes). Overall survival (OS) at 5 years was 48%, 31%, and 38% after ivBuCy, FB4, and FB2, respectively (p=NS). Active disease at SCT and poor-risk cytogenetics were the most significant factors predicting reduced survival in multivariable analysis with hazard ratios of 3.5 (p=0.0001) and 1.7 (p=0.04), respectively. Advanced age, secondary disease, donor and conditioning type had no prognostic significance. Myeloablative conditioning and RIC had similar outcomes when leukemia was in remission at SCT; estimated 5-year OS been 49%, 50% and 58% after ivBuCy, FB4, and FB2, respectively (p=NS). There was a non-statistically significant trend for lower non-relapse mortality (NRM) but higher relapse rate with FB2 resulting in similar OS in this setting. However pts with active disease could only be salvaged by myeloablative regimens (classical or modified). Among the later group, OS was 41% and 19% after ivBuCy and FB4, respectively, but no FB2 recipient survived (p=0.009). This was related to significantly higher relapse rates with the less intensive regimens in this setting (p=0.0005), while NRM was similar. These observations confirm with a longterm follow-up that RIC is associated with favorable outcome and low toxicity in pts in remission at SCT and therefore can be further studied in prospective trials comparing it to myeloablative regimens even in pts eligible for the later. However, RIC is a poor option for pts with active disease. Pts with active disease not eligible for standard myeloablation can still tolerate the modified myeloablative regimen (FB4) and a fraction can be salvaged. These observations merit further study in randomized prospective studies.

Download Full-text