After playing around with dispatch_io (https://gist.github.com/steipete/b22babbf3014e29c19f0), I ended up with this. Upside: Uses way less memory, controllable caching, similar performance, simpler code and supports priority donation implicitly since everything's sync.

NSData+PSPDFFoundation.m

static NSData *PSPDFCalculateSHA256FromFileURL(NSURL *fileURL, CC_LONG dataLength, NSError **error) {
    NSCParameterAssert(fileURL);

    NSData *shaData;

    int fd = open(fileURL.path.UTF8String, O_RDONLY);
    if (fd < 0) {
        if (error) *error = [NSError pspdf_errorWithCode:PSPDFErrorCodeUnableToOpenPDF description:@"Failed to open file for calculating SHA256."];
        return nil;
    }
    // Disable cache, since we only need this once.
    fcntl(fd, F_NOCACHE, 1);
    // Enable read-ahead so system fetches data while we calculate the SHA.
    fcntl(fd, F_RDAHEAD, 1);

    // Prepare SHA hash
    CC_SHA256_CTX ctx;
    CC_SHA256_Init(&ctx);

    // Start read and block until we are done.
    size_t const bufferSize = 1024*1025*4;
    char *buffer;
    if (!(buffer = malloc(bufferSize * sizeof(char)))) {
        if (error) *error = [NSError pspdf_errorWithCode:PSPDFErrorCodeOutOfMemory description:@"Unable to allocate buffer for calculating hash."];
        goto cleanup;
    }

    errno = 0; // just to be safe
    size_t bytes = 0;
    while (dataLength > 0) {
        ssize_t bytes_read_max = MIN(bufferSize, dataLength);
        ssize_t bytes_read = read(fd, buffer, bytes_read_max);
        if (bytes_read == -1) {
            if (errno == EINTR)
                continue;
        }
        if (bytes_read <= 0) {
            if (error) *error = [NSError pspdf_errorWithCode:PSPDFErrorCodeUnableToOpenPDF description:[NSString stringWithFormat:@"Failed to read data for calculating SHA256. errno: %d", errno]];
            goto cleanup;
        } else {
            CC_SHA256_Update(&ctx, (const void *)buffer, (CC_LONG)bytes_read);
        }
        bytes += bytes_read;
        dataLength -= bytes_read;
    }

    // Finalize SHA256 calculation unless there's an error.
    unsigned char sha256[CC_SHA256_DIGEST_LENGTH];
    CC_SHA256_Final(sha256, &ctx);
    shaData = [NSData dataWithBytes:sha256 length:CC_SHA256_DIGEST_LENGTH];

cleanup:
    free(buffer);
    close(fd);

    return shaData;
}