Hematopoietic stem cell transplantation (HSCT) is a curative treatment for patients with hematologic malignancies, some inherited metabolic disorders and bone ...
ª 2010 John Wiley & Sons A/S.
Clin Transplant 2011: 25: E68–E76 DOI: 10.1111/j.1399-0012.2010.01324.x
Second allogeneic hematopoietic stem cell transplantation: a treatment for graft failure Remberger M, Mattsson J, Olsson R, Ringde´n O. Second allogeneic hematopoietic stem cell transplantation: a treatment for graft failure. Clin Transplant 2011: 25: E68–E76. ª 2010 John Wiley & Sons A/S. Abstract: We evaluated the results in 20 recent patients treated with a second hematopoietic stem cell transplantation (HSCT) after graft failure (GF). There were 10 children 0.5 · 109/L for three consecutive days and platelet engraftment as platelet counts >30 · 109/L for five consecutive days without transfusions. Engraftment was verified by chimerism analysis using PCR amplification of variable number of tandem repeats (until 2003) and short tandem repeats. GF was defined as either failure to show neutrophil recovery and any evidence of donor origin DNA in chimerism analysis beyond day 30 after HSCT (primary GF) or complete loss
Re-transplantation after rejection of donor cells after initial engraftment (secondary GF). In all patients with GF, relapse of the underlying disease was excluded either by morphology examination of BM aspirates or by RTPCR of BCR-ABL or other relevant chromosomal aberrations.
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Statistics
Analysis was performed on August 10, 2009. Overall survival was calculated using the Kaplan– Meier method and compared with the log-rank test (40). Survival time was calculated from the second HSCT until death or until last follow-up, independent of the need of further HSCT. Transplantrelated mortality (TRM) and GVHD was estimated using a nonparametric estimator of cumulative incidence curves taking competing events in consideration. Categorical parameters were compared using the FisherÕs exact test and continuous variables were compared using the Mann–Whitney test.
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Results Engraftment and GF after first HSCT
Six patients developed GF without any signs of engraftment and were considered primary GF. Twelve patients had a transient donor engraftment (median 16 d [0–33] after HSCT) before suffering from GF median 109 d (37–386) after HSCT and these were considered secondary GF. Two patients developed late GF five and 15 yr after HSCT.
Fig. 1. Days to (A) neutrophil engraftment and (B) platelet engraftment according to type of conditioning before retransplantation for graft failure. Twenty patients treated with 26 hematopoietic stem cell transplantation (HSCT). Second HSCT n = 20, third HSCT n = 5, and fourth HSCT n = 1.
Second HSCT Engraftment. After the second HSCT, neutrophil and platelet engraftment occurred in 18 (90%) and 16 (80%) patients after a median of 20 (0–50) and 16 (0–130) d, respectively. No difference in engraftment rate and time to engraftment after second (n = 20) or third and fourth HSCT (n = 6) was seen. Neutrophile engraftment was significantly faster, and there was a trend for faster platelet engraftment in patients receiving the Flu/ATG protocol compared to the other protocols (p = 0.001 and p = 0.12) (Fig. 1A,B). Graft failure. The second HSCT was performed at a median of 43 d (9–270) after the GF and 172 d (43–5514) after the first HSCT. Eight patients (40%) suffered from a second GF (two primary and six secondary GF) at median of 41 d (17– 1579) after the second HSCT. Five of these patients were treated with a third HSCT 203 d
(33–1744) after the second HSCT, and for one patient the rejection was successfully reversed by treatment with rituximab and plasma exchange. One patient once again developed a GF after his third HSCT and received a fourth HSCT 895 d after his third HSCT. GF rates after second HSCT were 5/10 and 3/10 in patients with malignant and non-malignant diseases. No effect of stem cell source or cell dose was seen on engraftment. Among patients receiving the Flu/ATG protocol, 1/6 patients had a second GF compared to 4/9 receiving the Flu/Cy/ATG protocol and 3/5 given other protocols, p = ns. Survival and progression-free survival. Nine of the 20 patients (45%) died. The probability of survival was 65% (95% CI 45–85%) one yr and 60% (38– 82%) three yr after the second HSCT. No difference in survival was found between patients
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Fig. 2. Overall survival after second transplantation for graft failure according to (A) patient age, (B) malignant or non-malignant disorder, (C) conditioning protocols, and (D) progression-free survival after second hematopoietic stem cell transplantation (HSCT) in patients with a malignant disease.
transplanted with a new donor (n = 9) compared to those using the original donor (n = 11), 56% (24–88%) vs. 64% (36–92%) three yr after the second HSCT, p = ns. The three-yr survival was 70% (42–98%) for children 180 d) between the two transplants, 80% (55–100%) vs. 40% (10–70%), p = 0.08. TRM was 25% (6–44%) at 100 d and 30% (10– 50%) one yr after second HSCT. The only factor with a trend for affecting TRM was having a malignant disease, 40% (10–70%) vs. 10% (0– 28%) for non-malignant disorders at 100 d, p = 0.07. Progression-free survival for patients with a malignant disease was 24% at five yr after the second HSCT (Fig. 1D).
Re-transplantation after rejection Complications. The incidence of acute GVHD grades II–IV was 30% (6/20) after the second HSCT (33% in patients treated with the Flu/ATG protocol, 33% in those receiving Flu/Cy/ATG and 20% among patients receiving other protocols, p = ns) and 50% (3/6) after the third or fourth HSCT. Chimerism. GF was verified by chimerism analysis. After the first HSCT, most patients (n = 13) showed
