Allogeneic Hematopoietic Cell Transplant for Prolymphocytic Leukemia

Abstract

The poor prognosis of patients with prolymphocytic leukemia (PLL) has led some clinicians to recommend allogeneic hematopoietic cell transplant (HCT). However, the data to support this approach is limited to case-reports and small case-series. We reviewed the database of the Center for International Blood & Marrow Transplant Research to determine outcomes after allotransplant for patients with PLL. We identified 47 patients with a median age of 54 years (range, 30–75). With a median follow-up of 13 months, progression-free survival was 33% (95% Confidence Interval 20–47%) at 2 years. The most common cause of death was relapse or progression in 49%. The cumulative incidence of treatment-related mortality at 1-year post transplant was 28%. The small patient population prohibited prognostic factor analysis but these data support consideration of allotransplant for PLL. Further study of a larger population of patients is needed to determine which patients are more likely to benefit.

INTRODUCTION

Prolymphocytic leukemia (PLL) actually comprises two rare lymphoproliferative disorders:(1) 1) T-cell PLL (T-PLL) and 2) B-cell PLL (B-PLL). T-PLL expresses CD2, CD3, and CD 7 but not TdT or CD1a.(2) A specific cytogenetic abnormality, inv(14)(q11q32) or t(14;14)(q11q32) that results in a rearrangement of elements of the TCRAD locus with the oncogenes located within the TCL1 locus, occurs in most cases of T-PLL.(3–5) B-PLL has an immune phenotype similar to chronic lymphocytic leukemia (CLL); the cells express the pan-B antigens CD19, CD20, and CD22, but not CD5.(6)

PLL has a poor prognosis with standard therapies. Purine analogs are reasonably active and induce remission in about 50% of patients. Unfortunately, 90% of these responses are partial and the median duration of response is less than 1 year.(2, 7–11)

Monoclonal antibodies are active in PLL. Alemtuzumab induces remission in about 75% of patients with advanced T-PLL,(12) but the median response duration is less than 1 year.(13) Better results are achieved when alemtuzumab is given as initial therapy; nearly all patients respond and some remain in remission for years.(14) There is less experience with rituximab in B-PLL, with anecdotal reports of durable responses.(15)

Because of the poor prognosis with standard treatments, hematopoietic cell transplant (HCT) has been explored as therapy for advanced PLL. The largest published series included 11 patients with T-PLL treated with auto- or allotransplants. 3 of the 4 patients receiving allotransplant were alive up to 24 months following transplant.(12) Case reports also suggest the potential efficacy of allotransplants for PLL.(16-19) However, the efficacy of this approach remains uncertain. We, therefore, reviewed the databases of the Center for International Blood & Marrow Transplant Research (CIBMTR) to determine outcomes of allotransplants for PLL.

MATERIALS AND METHODS

Data sources

A formal affiliation of the research division of the NMDP, the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry led to establishment of the CIBMTR in 2004. The CIBMTR is a voluntary working group of more than 450 transplant centers worldwide that contribute detailed data on consecutive allogeneic HCTs to the Statistical Center at the Medical College of Wisconsin in Milwaukee or the National Marrow Donor Program Coordinating Center in Minneapolis. Approximately two-thirds of all active transplantation centers worldwide report data to the registry. The registry database includes information on 40–45% of all patients who have received an allotransplant since 1970, with annual updates. The CIBMTR collects data at two levels: Registration and Research. Registration data include disease type, age, sex, pre-transplant performance status, disease stage and chemotherapy-responsiveness, date of diagnosis, donor and graft type (bone marrow- and/or blood-derived stem cells), high-dose conditioning regimen, post-transplant engraftment, disease recurrence and survival, development of a new malignancy and cause of death. Requests for data on disease recurrence or death for registered patients are at six-month intervals. All CIBMTR centers contribute registration data on all patients. Research data are collected on subsets of registered patients selected using a weighted randomization scheme, including comprehensive pre- and post-transplant clinical information. Compliance is assessed by periodic audits and accuracy of data is ensured by computerized record checks, physician review of submitted data and on-site audits. Observational studies conducted by the CIBMTR are done with a waiver of informed consent and in compliance with HIPAA regulations as determined by the Institutional Review Board and Privacy Officer of Medical College of Wisconsin.

Patients

For the purposes of this analysis, the CIBMTR databases were queried for all patients with PLL treated by allogeneic HCT from 1995 through 2005. The diagnosis of PLL was made at the treatment center and there was no central review of histologic or immunophenotypic data.

Statistical analysis

Patient-, disease- and transplant- related factors were described. The product-limit estimator proposed by Kaplan-Meier was used to estimate the median and range of the follow-up time. Progression free survival is defined as survival without relapse, progression or persistent disease. Treatment failure events are disease relapse, progression or persistent disease or death and are summarized by a survival curve. Time to event is measured from the date of transplant. Probabilities of overall survival and progression-free survival were calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Patients were censored at date of last known follow-up. Cumulative incidence estimates were calculated for other endpoints to account for competing risks.

RESULTS AND DISCUSSION

47 patients with PLL received allotransplants at 29 centers (Table 1). Most donors (77%) were matched unrelated persons. 23 patient-unrelated donor pairs (64%) HLA matched at 8 out of 8 loci by high or low resolution typing at HLA-A, -B, and DRB1 were considered “well-matched.”20 12 patient –unrelated donor pairs were partially matched or mismatched and 1 pair was unknown. The median follow-up for all patients from the time of allotransplant was 13 months (range 6–81).

Table 1.

Characteristics of all the patients who underwent allotransplant for Prolymphocytic leukemia and reported to the CIBMTR, from 1995 to 2006

Variable	N eval	N (%)
Patient-related
Number of patients		47
Number of centers		29
Age, median (range), years	47	54 (30–75)
Age at transplant, years	47
31–40		4 (9)
41–50		11 (23)
>50		32 (68)
Male sex	47	31 (66)
Race white	47	41 (87)
Karnofsky score at transplant	40
≤80%		10 (25)
> 80%		30 (75)
Disease-related
Interval from diagnosis to transplant (months)	47	11 (2–78)
Immunophenotype	47
B cell PLL		11 (23)
T cell PLL		21 (45)
PLL (Type unknown, confirmed with centers)		15 (32)
Splenectomy	46
Yes		6 (13)
No		40 (87)
Disease stage at HCT	45
Complete remission		16 (36)
Partial remission		8 (18)
Refractory		21 (46)
Transplant-related
Donor/recipient gender match	47
M-M		22 (47)
M-F		12 (26)
F-M		9 (19)
F-F		4 (9)
Donor	47
HLA-identical sibling		11 (23)
Unrelated		36 (77)
Donor-recipient HLA match****	47
Matched sibling		11 (24)
Well matched		23 (49)
Mismatched		12 (25)
Unknown		1 (2)
Donor-recipient CMV status	45
+/+		11 (24)
+/−		3 (7)
−/+		15 (33)
−/−		16 (36)
Conditioning regimen	47
≥9 mg/kg busulfan or > 500 cGy radiation (Myeloablative)		19 (40)
<9 mg/kg busulfan or < 500 cGy radiation (Reduced Intensity)		14 (30)
Neither (Melphalan or Fludarabine based regimens)		14 (30)
Graft type	47
Bone Marrow		15 (32)
Peripheral Blood Progenitor Cells		31 (66)
Umbilical Cord Blood		1 (2)
Year of transplant	47
1995–1996		3 (6)
1997–1998		2 (4)
1999–2000		9 (19)
2001–2002		5 (11)
2003–2004		12 (26)
2005–2006		16 (34)
GVHD prophylaxis	47
MTX+CsA ± others		18 (38)
FK506+MTX ± others		9 (19)
CsA ± others		8 (17)
FK506 ± others		10 (21)
T-cell depletion		2 (4)
Median follow-up of survivors, months	14	13 (6–81)

Abbreviations: PLL= prolymphocytic leukemia; GVHD = graft versus host disease; MTX = methotrexate; CsA = cyclosporine; FK506 = tacrolimus

^****Well matched was defined as no known disparity at HLA A,B,C,DRB1, partially matched as one locus known or likely disparity with their donors and mismatched as ≥2 locus disparity.

Grade 2–4 acute graft versus host disease (GVHD) developed in 52% (95% confidence interval (CI) 38–66%) of transplant recipients. The 1-year incidence of chronic GVHD was 42% (CI 28–57%). The cumulative incidence of treatment-related mortality at 1-year post transplant was 28% (CI 16–42). One year incidence of relapse or progression was 39% (CI 25–53). Of the 33 deaths, 16 (49%) were due to progression of leukemia, 5 (15%) were from GVHD, and 4(12%) were from infection.

With a median follow-up of survivors of 13 months (range, 6–81), the 1 year progression-free survival (PFS) is 33% (CI 20–47) (Figure 1). The 1 year overall survival (OS) is 48 % (CI 33–62) with a median OS of 11.2 months (CI 8–14). There was no significant differences in 1 year OS between patients treated with non-myeloablative versus myeloablative transplant, sibling versus matched unrelated donor transplant, age greater than 54 versus age 54 years or less, B-cell versus T-cell PLL, or in first CR versus not in first CR. Neither was there a difference in 2 year OS between patients with either acute or chronic GVHD compared to those without GVHD.

Figure 1.

Probablity of A) progression-free survival and B) overall survival after allotransplant for prolymphocytic leukemia (N = 47).

Median PFS for the 21 patients with T-PLL was 5.1 months and 3.5 months for the 11 patients with B-PLL. The 16 patients in CR at transplant had a median PFS of 8.9 months and the 34 patients transplanted with HLA-matched sibling or HLA-well-matched unrelated donors had a median PFS of 5.2 months. 5 patients were still alive and in remission at the time of data analysis.

Although most patients with advanced PLL have poor survival, our data demonstrates that approximately one third of patients are alive and progression-free at 1 year. Consistent with some case-reports indicating long-term progression-free survival in a minority of select patients,(19, 20) and since there is no other effective therapy that provides durable remissions, patients with PLL that are eligible for SCT should consider this option.

Our study is too small and with too heterogenous of a population to explore potentially important questions with regard to which patients may ultimately benefit from an allotransplant. For example, we could not perform a multivariable analysis to determine which risk factors, if any, correlated with outcomes. Nonetheless, our data indicates that at least some patients may derive sustained benefit from an allotransplant. More and larger studies would be required to help identify which patients those would be.